Recent advances and perspectives of postoperative neurological disorders in the elderly surgical patients

Abstract Postoperative neurological disorders, including postoperative delirium (POD), postoperative cognitive dysfunction (POCD), postoperative covert ischemic stroke, and hemorrhagic stroke, are challenging clinical problems in the emerging aged surgical population. These disorders can deteriorate functional outcomes and long‐term quality of life after surgery, resulting in a substantial social and financial burden to the family and society. Understanding predisposing and precipitating factors may promote individualized preventive treatment for each disorder, as several risk factors are modifiable. Besides prevention, timely identification and treatment of etiologies and symptoms can contribute to better recovery from postoperative neurological disorders and lower risk of long‐term cognitive impairment, disability, and even death. Herein, we summarize the diagnosis, risk factors, prevention, and treatment of these postoperative complications, with emphasis on recent advances and perspectives.

POD is frequently linked to anesthesia. 2 Compared to dementia which chronically deteriorates brain function, POD is usually acute, transient, and presenting common causative factors. 3 It contributes to prolonged hospitalization, increased mortality rate, and reduced long-term quality of life, which adds an additional burden to patients and families.
Besides DSM-5 listed in Table 1 and ICD-10 diagnostic criteria which supplements a disturbance in sleep-awake cycle including insomnia, reverse of sleep-awake cycle, various assessment tools have been developed to recognize POD. 4 The CAM-ICU is a screening tool which consists of the assessment of four characteristics: 1) acute onset and fluctuating course of mental state, 2) inattention, 3) disorganized thinking, and 4) altered level of consciousness. 5 Delirium is diagnosed when both characteristics 1) and 2) are satisfied with 3) or 4) electively satisfied. 6

| POCD
Postoperative cognitive dysfunction, also defined as postoperative neurocognitive disorder (pNCD), 7,8 is characterized by cognitive decline persisting for more than 30 days but less than 12 months following surgery. Unlike POD (Table 2), consciousness, orientation, and attention are not obviously affected in POCD. 9 However, patients can still manifest impairment in memory, perceptual function, and language. 9,10 The incidence increases among the elderly, especially those over 60 years old. 11 For elderly patients, cognitive decline may result in prolonged hospitalization, reduced quality of life, even increased mortality, which has been neglected in the assessment of patient's prognosis, especially for those undergoing general anesthesia and surgery. 12 The diagnosis criteria for POCD are more complex than for POD, as POCD requires a subjective impression of postoperative cognitive decline in neuropsychological test. 13

| Postoperative covert stroke
Cerebrovascular disease, a leading global cause of death and disability with approximately 6.2 million deaths due to stoke, is estimated to become the second leading cause of death by 2030. 14 According to a systemic analysis for the Global Burden of Disease Study, the mortality rates caused by stroke range from 30.6% to 48.3% 15 and are significantly related to operations. 16 Covert stroke has been increasingly recognized over the years. It represents brain infarcts with silent and subtle manifestations that can be detected on brain imaging. 17,18 Covert stroke may contribute more to poor outcomes and prognosis in elderly patients presenting cognitive decline, as its subtle manifestation can lead to ignorance of cognitive symptoms. 19 The incidence of postoperative covert stroke has gradually increased due to the aging population. So far, only a few studies have examined its mechanisms. 20 Little is known about perioperative covert stroke except its association with substantially increased mortality. 21 One multicenter prospective cohort study reported that postoperative covert stroke was found in 7% among 1114 participants over 65 years old who underwent inpatient, elective, noncardiac surgery, which were assessed with brain magnetic resonance imaging (MRI) after surgery and Montreal Cognitive Assessment (MoCA) on preoperative baseline and 1-year follow-up. 22 Among the patients with a complete 1-year follow-up, cognitive decline after surgery occurred in 42% of participants who had postoperative covert stroke and 29% of participants who did not have postoperative covert stroke. 22 In addition, another study suggested that covert stroke can increase the risk of POD, overt stroke, or transient ischemic attack (TIA) during one-year follow-up. 22

| Hemorrhagic stroke
Although hemorrhagic stroke comprises only 20% of all strokes, the perioperative hemorrhagic stroke could detrimentally deteriorate patients' recovery and prognosis. 23 According to the American Heart Association (AHA) and the American Stroke Association (ASA), 24,25 hemorrhagic stroke is divided into the following conditions: 1) focal bleeding in brain parenchyma and 2) in subarachnoid space or ventricular space due to rupture of blood vessel other than trauma. Perioperative hemorrhagic stroke may occur after cerebral hyper-perfusion due to a sudden surge of blood pressure (BP) for a certain amount of time. 26 Hypertension is the most common risk factor for hemorrhagic stroke. 27 Most anesthetics induce hypotension, so they are unlikely to provoke hemorrhagic stroke while under anesthesia. 28 However, if postoperative hypertension persists for several hours, it can lead to certain condition linked to a sudden surge of cerebral perfusion. 29 What discussed above is a brief introduction of four major types of postoperative neurological disorders with current understanding, which present disorientation, memory deficit, changes in awareness and attention from the baseline. Cognitive decline and poor prognosis of elderly patients after surgery have been an increasing concern around the world. With few studies on postoperative neurological disorders, the mechanisms and pathophysiology remain unknown, 30,31 especially for POD, POCD, and covert stroke. Besides, various manifestations of postoperative neurological disorders add more difficulties for research. As postoperative complications become increasing concerns, the mechanisms, prevention, and management are focus points that still need further research.

| RIS K FAC TOR S OF ACUTE P OS TOPER ATIVE NEUROLOG IC AL DISORDER S
The exact mechanisms and pathophysiology of POD, POCD, and postoperative stroke are unclear. In the following paragraphs, we discuss potential risk factors of postoperative neurological disorders.

| Risk factors of POD and POCD
It is commonly accepted that interactions between predisposing factors and precipitating factors play an important role in the occurrence of postoperative neurological disorders. 32 The smaller vulnerability a patient has, the less occurrence of neurological disorders. 32 For example, as advanced age is a predisposing factor, patients over 65 years old may present POD or POCD when exposed to only a few precipitating factors. 33 On the contrary, younger patients exposed to the same precipitating factors may not experience POD or POCD. The recent evidence-based risk factors including some novel candidates for POD as listed in Table 3. 32 POD and POCD share almost the same risk factors based on current limited researches. 34 Moreover, SARS-CoV-2 (COVID-19) infection, a new uprising disease, has been found to be a potential novel risk factor of POD and POCD during the pandemic in the past two years, which is related to an accelerated onset with neurological manifestations 35 and deterioration of cognitive decline. 36

| Risk factors of postoperative stroke
Postoperative stroke remains one of the most serious complications after surgery. As for both ischemic stroke and hemorrhagic stroke, risk factors include conventional vascular risk factors, the type of surgery, and other perioperative events (Table 4)

DSM−5 Diagnostic criteria for delirium
A disturbance in attention (reduced ability to direct, focus, sustain, and shift attention) and awareness (reduced orientation to the environment). A disturbance that develops over a short period (usually hours to a few days) represents a change from baseline attention and awareness and fluctuates in severity during the day. An additional disturbance in cognition (memory deficit, disorientation, language. visuospatial ability, or perception). The disturbances in Criteria 1 and 3 are not better explained by another pre-existing established or evolving neurocognitive disorder and do not occur in a severely reduced level of arousal, such as coma. There is evidence from the history, physical examination, or laboratory findings that the disturbance is a direct physiological consequence of another medical condition, substance intoxication or withdrawal (due to a drug of abuse or to a medication), or exposure to a toxin, or is due to multiple etiologies. base studies, which will be further discussed.

| BP and stroke
Blood pressure fluctuation is an important risk factor for postoperative stroke. 39 Emergency surgeries raise the incidence of neurological disorders and even affect long-term cognitive functions. 40  Hybrid procedure 130 Intraoperative bleeding 136

Duration of surgery 126
Bispectral index (too low or too high) 127 Intraoperative electrolyte disturbance 128 Hyperthermia or hypothermia 137,138 The rate of decline in intraoperative hemoglobin concentration

| Nonpharmacological interventions
Based on the studies of HELP, the multicomponent nonpharmacological intervention significantly reduces the incidence of delirium, including reorientation (using orientation calendar, clocks), early mobilization, promotion of sleep cycle, adequate hydration, visual and hearing aids, and increased supervision in hospital. 53 If implemented by a skilled interdisciplinary team, these measures are effective against POD. 54 Apart from common contents of HELP, a recent clinical trial has found that tailored, family-involved HELP could be beneficial for reducing POD, maintaining, or improving cognitive function, which may increase the implementation of this program. 55 During the operation, however, the EEG (electroencephalography)-guided anesthetic administration, compared with usual care, failed to decrease the incidence of POD. 56

| Pharmacological interventions
Although several clinical trials have run various pharmacologic measures, there is a lack of strong evidence for effective prevention.
One network meta-analysis demonstrated that haloperidol plus lorazepam might be the best treatment, while ramelteon may be the best preventive medicine for POD. 57 Besides, a recent randomized clinical trial has evaluated the effectiveness of tropisetron and found that tropisetron could decrease the incidence of delirium after noncardiac procedures in adults. 58

| Preoperative interventions
The evaluation of patients' baseline is important for the identification and prevention of POCD. Neuropsychological tests should be used before and after operations. 62 Also, cognitive training and exercise 63 have been proven to be beneficial for preventing POCD occurrence. 64 Besides, Lu et al. found that pretreatment of parecoxib sodium combined with dexmedetomidine can decrease the incidence of POCD in patients undergoing arthroscopy by over 10%. 65 These interventions should be particularly considered in high-risk patients.

Risk factors Reference
Preoperative factors compared with total intravenous anesthetics. 67 Also, propofol may have a significant advantage in reducing POCD incidence compared with dexmedetomidine and midazolam sedation in elderly patients, in which midazolam has the highest inhibitory effects on cognitive functions. 68 As for monitoring measures, one trial has shown a decreased incidence of short-term POCD with bispectral index (BIS)-guided deep anesthesia during the operation. 69 Lastly, it has been suggested that postoperative management, including early identification and treatment of postoperative complications, may decrease the risk of POCD, which will be discussed in the treatment section. All interventions discussed above are listed in Figure 2

| Nonpharmacological measures
Nonpharmacological measures are beneficial for both preventing and treating POD, 80 including reorientation, early mobilization, promotion of sleep cycle, adequate hydration, and visual and hearing aids. They can modify and create a safe and calm environment for patients.

| Pharmacological measures
There is no strong evidence for pharmacological management of POD, although the use of dexmedetomidine resulted in more ventilator-free time at 7 days among patients with agitated delirium in the intensive care unit. 81 Medications are generally applied for delirium-associated behaviors. Two types of medications are frequently used, that is, antipsychotics and benzodiazepines. 82 For agitation with perceptual disturbance or sleep-wake cycle abnormalities, antipsychotics can be useful. 83 Nevertheless, patients with POD, which is more common in advanced age, may respond poorly to antipsychotic medications. 84 Benzodiazepines are historically used to sedate patients with delirium for decades.
However, evidence suggests that benzodiazepines may increase the risk and duration of delirium, especially in elderly patients. 85 Thus, benzodiazepines should be mainly used in the treatment of agitation associated with sedative withdrawal. 82 Another randomized trial showed that the addition of lorazepam to haloperidol resulted in a significantly reduction in agitation at 8 hours in hospitalized cancer patients with agitated delirium. 86 Given the above evidence, pharmacologic treatment is not strongly recommended but can be used to treat severe agitation and life-threatening POD complication.

| Treatment of POCD
Preventive interventions discussed above can also be used for the treatment of POCD. Several preclinical and clinical studies suggested that targeting postoperative neuro-inflammation 87-91 may be a potential way to treat POCD. There are some medications used in the clinical trials attempted to block the process of neuroinflammation.
The cyclooxygenase-2 (COX-2), which is responsible for catalyzing the conversion of arachidonic acid to pro-inflammatory prostaglandins 92 and increasing blood-brain barrier (BBB) permeability, 93,94 is considered to be an important mediator of neuroinflammation and thus a potential target for POCD treatment. Moreover, a metaanalysis suggested that the administration of parecoxib was effective in treating early POCD within 7 days and reducing interleukin-6 (IL-6) and S100 calcium-binding protein B protein (S100β) concentrations within 2 days after operations. 95 Other anti-inflammatory medications, such as minocycline 96  which is considered as a treatment option for postoperative stroke. 108 Besides, studies have expanded the therapeutic window up to 24 hours after symptom onset for patients with a small core and large penumbra. 109 New devices continue to be developed for reaching distal branches, 110 which may provide standard treatment for perioperative stroke.

| Treatment of postoperative hemorrhagic stroke
Some clinical trials suggested various effective treatment methods for hemorrhagic stroke, including the control of high BP and intracranial pressure (ICP), and treatment of complications and intracranial hemorrhage, 111 which are important treatment methods for hemorrhagic stroke. We will discuss the most effective methods below.

| Controlled BP
Patients with hemorrhage usually present high BP. High SBP has been associated with neurological deterioration and death, 112 which should be gradually reduced by using antihypertensive drugs such as CCB and ACEI. The ASA recommended that for patients presenting with SBP between 150 and 220 mmHg, an acute and aggressive reduction of SBP is safe and beneficial for functional outcomes. 112 However, some clinical trials found no significant relationship between SBP reduction and hematoma expansion or outcome. 113 The goal and effect of BP control in postoperative hemorrhagic stroke need to be elucidated in future studies.

| Interventions to control intracranial pressure (ICP)
The initial treatment should include elevating the head of the bed to 30° and the patients' head facing midline to avoid excessive flexion or rotation of the neck. 114 Then, osmotic agents (mannitol and hypertonic saline) are given; for example, 20% mannitol is given at 1.0-1.5 g/kg. 115

Minimally invasive approach
The practice of open craniotomy is complicated with brain tissue damage and related complications because it requires a large bone flap and exposure of the brain tissue. On the contrary, a minimally invasive approach with thrombolysis is safer, more feasible, and more efficacious. 124 However, it still showed no significant benefit of long-term functional outcome than conservative treatment based on clinical trials. 124 In summary, decompressive craniectomy and hematoma evacuation are performed more frequently for hemorrhagic stroke in patients with Glasgow Coma Scale (GCS) scores of 8 or less and large hematomas. These procedures reduce mortality and may improve functional outcomes. 125

| CON CLUS I ON AND FUTURE REMARK S
Postoperative neurological disorders are common complications without effective treatment that exert an enormous burden on patients, their families, hospitals, public resources, and society. The existing acknowledge of risk factors provides certain information to guide possible effective interventions that may need more repeating trials, but further interventional research is urgently needed to improve the outcomes or prognosis for hospitalized patients who experience the condition. Early prevention is likely to be more effective than treatment for prognosis. Thus, further prospective trials should gain deeper insight into uncertain mechanisms and contributing factors underlying these neurological disorders, avoiding simple risk factor evaluation, and validating possible prognostic models for interventional research.
Significantly, dexmedetomidine may be an effective medication for the prevention of POD and POCD as mentioned in multiple trials, which should be considered in future research. As for covert stroke, early identification may be more effective, likely given priority to in further research.

CO N FLI C T O F I NTE R E S T
The authors declare to have no potential conflicts of interest. All data included in this study are available upon request by contact with the corresponding author.