The Role of Perioperative Acupoint Stimulation in the Prevention of Postoperative Cognitive Dysfunction

This is an open-access article, published by Evidence Based Communications (EBC). This work is licensed under the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium or format for any lawful purpose.To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. From Department of Anesthesiology, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, China.

ostoperative cognitive dysfunction (POCD) is a common surgical complication which is more likely to appear in the geriatric population.Over the last a few decades, much progress in the field of both traditional Chinese and western medicine showed that perioperative acupoint stimulation therapy has effects on both reducing the dosage of anesthetics and preventing POCD in patients (1)(2)(3)(4).We will review the causes, diagnosis and prevention strategies of POCD, and make recommendations regarding the approach of perioperative acupoint stimulation on at-risk patients to minimize the incidence of POCD in this article.

An Overview of POCD
In 1955, Based on an analysis of 1193 elderly patients, Bedford (5) found that no less than one-third of them behaved as having a cognitive dysfunction or varying degrees of dementia after undergoing a surgery.Since then, this kind of frequent neurological complication which may cause the damage of a wide variety of cognitive functions, such as memory, attention, speed of information processing, executive function and comprehension skill, has been named POCD (6,7).
The clinical manifestations of POCD are quite diverse, and till now, the definite mechanisms whereby surgical procedures and general anesthesia contribute to POCD are currently poorly understood.What can be ensured is that risk factors for the development of POCD include but not limited to three major aspects: patients' physical conditions, surgical procedures and general anesthesia (8).Besides, although aging itself is not regarded as a kind of disease, but it is already universally accepted as an independent risk factor of POCD (9).Dokkedal (10) proposed that POCD could be diagnosed by a test battery, which contain the following five components: 1) the fluency in category, recitation digit span by both; 2) forward and; 3) backward, recall a 12-items list; 4) immediate and; 5) delayed.There are also some more kinds of examinations such as Mini-Mental State Examination (MMSE), Wechsler Memory Seale (WMS) and Minnesota Multiphasic Personality Inventory (MMPI), while Saczynski (11) pointed that Montreal Cognitive Assessment (MoCA) shows more sensitivity than MMSE in the assessment of advanced cognitive function.
Traditionally, β-amyloid (Aβ) is seemed to be a kind of biochemical marker which can be used in the diagnosis of Alzheimer's disease (AD).However, the research performed by Evered suggested that some anesthetic agents may increase the risk of AD in susceptible patients, which made biomarkers of AD have been found to be altered after anesthesia and surgery, highlighting the possible role of cerebrospinal fluid (CSF) biomarkers in predicting POCD in different surgical settings (12).Some other researchers fingered out that several kinds of biochemical markers which are interrelated to inflammation have contact with POCD as well.For example, the one who has a low preoperative density of immunoglobulin M (IgM), the possibility for him to emerge from POCD is significantly increased (13).S100A8 protein can stimulate NF-kappaB signaling pathway and change the expression of genes to raise the content of tumor necrosis factorα (TNFα) and interleukin-1β (IL-1β) by the activation of Toll-like receptor 4 (TLR4).The result of changing this pathway will be the promotion of inflammation of the nervous system and finally developing POCD (14,15).
Several decades have already passed since the first time POCD got its name, but nowadays, we still have not defined its causes completely.Based on our limited understanding of POCD, some anesthesiologist found that instead of general anesthesia, continuous epidural anesthesia or anesthetizing under bispectral index (BIS) monitoring to reduce the dose of anesthetic drugs may have a positive effect on prevention of POCD (16,17).In animal experiments, the complying of preoperative environmental enrichment (PEE) showed improved results of abnormal object recognition test and also prevented the progress of inflammation, showing that the more external stimulation the brain received, the less chance it had to occur POCD (18).

Medicine and POCD
With less progress on their own way, some researchers set their sights on traditional Chinese medicine with a quite different philosophy system from which we can infer that acupuncture therapy for the treatment of stroke may also have an effect on POCD.Although the exact role of the therapy by traditional Chinese medicine of POCD remains elusive, but from the view of traditional Chinese medicine, POCD can be classified as a kind of deficiency syndrome which is caused by spleen and kidney deficiency, blood deficiency, meridians emptiness, and even the pathogenic wind.The history of acupuncture can be dated back to thousands of years ago.The Canon of Medicine reviewed that acupuncture therapy can be used to dredge the meridians, regulate Qi and Blood to relieve pain, numbness and swelling.Since the 1950s, research and application of perioperative stimulate acupuncture are mainly concentrated in anesthesia and analgesia, its underlying biological mechanisms are largely unknown.So far, numerous studies have confirmed the effectiveness of assisted anesthesia by acupuncture, which can reduce the amount of narcotic drugs, mitigate stress, reduce complications and improve the patients' quality of life (1).
With the acupoint stimulation, one research on Sprague-Dawley rat models of focal cerebral ischemia-reperfusion injury showed that the volume of cerebral infarction deeply decreased from (61.72 ± 7.12)% to (22.37 ± 4.42)% (20), which was probably based on the mechanism that acupoint stimulation showed the effect of inhibiting the intake of oxygen and glucose on neurons by monitoring its difference of oxygen and glucose contents between blood samples of arterial and jugular bulb (Da-jvO2, Da-jvGlu) (21) (Table ).

The Effect of Perioperative Acupoint Stimulation
Acupoint stimulation, especially the transcutaneous electrical acupoint stimulation (TEAS), could reduce the concentration of epinephrine and norepinephrine in patients (2), which means that the realization of curative effect may be caused by alleviating surgery-related stress response on the body.Compared with conventional anesthesia, anesthesia with acupoint stimulation together made the amount of narcotic drugs, extubation and recovery time had a significantly reduction (1,22), which helped anesthetists to optimize management of patients' perioperative blood pressure (23).In another research, a conclusion can be inferred that because of the perioperative acupoint stimulation, concentrations of markers of brain injury S-100β protein in serum are also declined (24).Acupoint stimulation produces the protective effect on brain by the above-described action during the perioperative period (25), thus contributing to prevent the occurrence of POCD.
There are further studies have shown that compared with the use of continuous wave electrical stimulation, the using of 2HZ-100HZ density waves performed better that may be related to the effects of fatigue of acupuncture points to electrical stimulation (3).In recent years, some clinical studies indicated that compared with the patients received general anesthesia, the incidence of POCD in those patients who received TEAS during the surgery was significantly decreased at about one to four days after surgery, but there was no significant difference in longterm (≥5 d) incidence (2)(3)(4).While the DSM-Ⅳ (26) states that it can only be diagnosed as POCD if the cognitive disturbance doesn't meet the criteria for delirium, dementia, or amnestic disorder, and in further species, an individual must has a new onset of deficits in at least two areas of cognitive functioning lasting for a period of at least 2 weeks.So, which kind of cognitive dysfunctions we observed within 4 days after surgery and how does TEAS really work on it still remains further studies to finger it out.Some scholars' analysis showed that after a variety of surgical procedures, incidence of POCD at 7 days later was evidently higher than 30 days after (27).The result suggested that cognitive abnormality in the early postoperative stage was probably caused by stress reaction, and pharmacological effects of narcotic drugs and their effects on the nervous system had not been fully recovered.Therefore, the evaluation of POCD should be done after 3 months of the surgical procedure, so as to provide a reliable result and rule out of the impact of these factors (12).

Probable Mechanism of Acupoint Stimulation
Studies have shown that stimulation of Baihui and Neiguan can improve blood perfusion of brain and further strengthen the microcirculation and metabolism.The stimulation can also lower the expression of some kinds of inflammatory factors such as cyclooxygenase2 (COX-2), TNF and IL by inhibiting NF-kappaB signal transduction pathway, in order to contribute to the restoration of the cell function of central nervous system (28).
Acupuncture on Hegu can cause the activation of brain function within a broader region, which will further showed significant sedative and analgesic effects (29).
Needling Tsusanli can regulate body movement, sensation, language, memory, learning, and the spirit and visceral activities by activating the brain mainly in the temporal lobe and some parts of the frontal, insula, parietal lobe, lingulate gyrus and cerebellum (30).The concentrations of TNF, IL-6 and human high-mobility group box-1 (HMGB1) in serum, TNFα mRNA and protein levels in spleen were both down regulated, which showed the anti-inflammation effects of this acupoint (31)(32)(33).In addition, intervention by TEAS on Hegu and Tsusanli can reduce the metabolism of glucose and oxygen in the brain during the perioperative period, thereby increasing the tolerability of brain ischemia (21).Although there are still some disputes on whether lactate could be energy substrates of brain, some researchers have already noticed that TEAS may protect brain cells by affecting the uptake of lactate (34).In animal experiments, it showed that these two acupoints had the potential of protecting from brain injury by increasing thalamus blood flow and improving oxygen delivery obviously from (84.33 ± 50.65) PU to (161.80 ± 73.65) PU under deliberated hypotension when mean arterial pressure (MAP) decreased to 40% of baseline for at least 1 hour (35).
At present, except inflammatory reactions, oxygen radical has also been known as playing an important role in the genesis and development of POCD (13,36).TAES can increase superoxide dismutase (SOD) level, inhibit malondialdehyde (MDA) gather and play a role to protect brain function.SOD is a kind of antioxidative enzyme which can scavenge oxygen radicals, thereby blocking the lipid peroxidation chain re-action (36).MDA is a metabolic product of the peroxidation of unsaturated fatty acid in biofilm initiated by oxygen radicals.With the lower concentrations of MDA and hypersensitive C-reactive protein (hs-CRP) caused by TEAS, it can be inferred that TAES may play a role in improving postoperative cognitive function by reducing oxidative stress reactions (32).

Conclusion
So far, researches on effects of acupuncture stimulation on POCD are mostly in non-cardiac surgery patients, while the traditional view is generally considered that cardiopulmonary bypass (CPB) is a risk factor for the occurrence of POCD (37).But one research with the patients treated with off-pump coronary artery bypass grafting (OPCABG) showed that even though without CPB and TEAS therapy, the incidence of POCD was still not significantly decreased (38).This happens probably because, in such kind of patients, chronic cardiovascular diseases are commonly found with them and effects of long-term cerebral perfusion is beyond the extent of acupoint stimulation can alleviate.Chronic cardiovascular disease may also be an independent risk factor of POCD which is similar to the age.
In summary, to confirm the effects of acupoint stimulation therapy on POCD, some more researches and clinical practice are still needed, and larger, more adequately powered studies are also required to draw the best solution to stimulate acupuncture points, which may also become a breakthrough on mechanisms of POCD.
No potential conflict of interest relevant to this review was reported.
The Role of Perioperative Acupoint Stimulation in the Prevention of Postoperative Cognitive Dysfunction