Effect of dexmedetomidine on postoperative cognitive dysfunction in elderly patients undergoing orthopaedic surgery: study protocol for a randomized controlled trial

Postoperative cognitive dysfunction (POCD) is defined as the patient’s cognitive dysfunction following surgery and anaesthesia, which mainly manifests as a decline in cognitive function and memory. The severely affected patients may experience a reduced capacity for social interaction and irreversible cognitive impairment [1]. It has been reported that the incidence of POCD in patients over 60 years old is 25 to 40% [2]. The incidence of POCD in patients undergoing lower extremity arthroplasty is 41–75% [3]. POCD, a severe postoperative complication, may result in increased time in bed and the risk of pulmonary infection. In addition, postoperative mortality will increase in severe cases [4]. Therefore, it is crucial to find a proper perioperative drug to prevent POCD.

Dexmedetomidine (DEX), a new α2 adrenergic receptor agonist, induces sedation, hypnosis and analgesia effects. In recent years, studies on DEX have been extensive, especially in research on neuroprotection [5]. There are increasing evidences that DEX plays a significant role in improving POCD [6‐8], but the mechanism is uncertain. Studies have shown that the mechanism by which DEX improves POCD includes many factors, such as inhibition of the inflammatory response [9] and apoptosis [10]. However, due to the pleiotropic regulation of DEX, the molecular mechanism and specific regulatory pathway of the neuroprotective effects of DEX should be further confirmed.

Recently, there has been increasing concern about the effect of DEX on postoperative immune function [11‐13]. T helper 17 (Th17) cells and regulatory T cells (Treg cell) are a subset of CD4_T cells, which have been shown to participate in the development of many inflammatory diseases, including systemic lupus erythematosus and multiple sclerosis (MS) [14, 15]. A study showed that vitamin D can improve POCD by regulating the Th17/Treg cell balance [16]. Another study reported that α7nAchR can improve POCD by regulating the Th17 response [17]. Additionally, a previous clinical study found that peripheral Th17/Treg imbalance was involved in the development of ischaemic stroke in elderly patients [18]. Another study reported that the Th17/Treg balance shifting to the Th17 cell played a role in the development of cognitive impairment in traumatic brain injury patients [19]. The above results revealed that the balance of Th17/Treg cells might play an important role in POCD. Moreover, previous literature showed that Treg cells can alleviate the damage to the blood-brain barrier induced by ischaemic stroke [20]. Matrix metalloproteinases (MMPs) are the main mediators that reflect the loss of blood-brain barrier (BBB) integrity, and they have been proven to be involved in the pathological process of many diseases such as AD and cerebral ischaemia reperfusion injury [21, 22]. Elevated MMP-9 levels in patients after surgery may lead to the occurrence of POCD [23]. However, whether DEX can improve POCD by alleviating the imbalance of Th17/Treg cells remains unknown.

The present study aims to verify whether DEX can improve POCD by regulating the balance of Th17/Treg cells in patients undergoing lower extremity arthroplasty. Health economic indicators (hospitalization duration and costs) will provide favourable evidence of DEX improving POCD in patients undergoing lower extremity arthroplasty. This trial will provide further trustworthy support for the intraoperative application of DEX to prevent the occurrence of POCD.

This protocol was guided by the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Checklist (Additional file 1). The trial received ethics committee approval from Hebei General Hospital, China (ethics approval no.2019–48), and it was registered on ClinicalTrials.​gov (No. ChiCTR2200055802). The trial registration dataset is presented in Additional file 2. Publications associated with the trial will be formatted according to the CONSORT Statement (Additional file 3).

POCD, a common postoperative complication, refers to a decline in nervous system function, which might eventually lead to permanent brain damage [26]. As mentioned earlier, a higher incidence of POCD has been confirmed in patients undergoing lower extremity joint replacement surgery, but it remains hard to treat effectively. Researchers have proposed various hypotheses to reveal the mechanisms of POCD, including neuroinflammation, oxidative stress, autophagy disorder, impaired synaptic function and a lack of neurotrophic support [27]. However, the specific mechanism of POCD is still ambiguous.

Based on previous studies, surgery activates the host’s innate immune system, leading to peripheral inflammation [28, 29]. Therefore, we note that the changes in patients’ immune function due to surgery and anaesthesia may be an important factor affecting POCD. Treg cells, a special subset of T cells, play an important role in suppressing inflammation and inhibiting autoimmune processes [30] and appear to be an endogenous protective mechanism against brain inflammation after ischaemic stroke [20]. Th17 cells, also a subset of CD4 T cells, are involved in the pathological process of various central inflammatory diseases [31, 32]. A study showed that Th17 cells played a major role in the pathogenesis of neurodegenerative diseases [33]. According to the above studies, the imbalance of Th17/Treg cells may activate the inflammatory response and promote the release of inflammatory factors, which results in the occurrence and development of POCD.

Impairment of cognitive function may also be attributed to disruption of the BBB [34, 35]. The major components of the BBB include endothelial cells, astrocytes, pericytes and the extracellular matrix (ECM), which provide structural and functional support for the BBB. The ECM, one of the important components of the BBB, is destroyed by MMPs. MMP-9, an indicator of the damage of BBB, plays a vital role in the disruption of the BBB, neutrophil infiltration and brain injury after ischaemia stroke [36]. After the breakdown of the BBB, a large number of immune cells enter the brain, thus beginning a vicious cycle that causes long-term brain damage and disruption of neurological function.

Fortunately, many reports showed that DEX might improve postoperative immune function in patients. Researchers have reported that DEX can maintain the Th1/Th2 balance to protect immune function [12]. According to a recent study [13], DEX could regulate the CD4/CD8 balance in patients undergoing hip arthroplasty to protect immune function. Additionally, one study confirmed that DEX alleviated cognitive impairment by modulating Th1/Th2/Th17 polarization and reducing disruption of the BBB in a mouse experimental sepsis model [37]. Another study reported that Treg cells can alleviate the loss of BBB integrity after ischaemia stroke [20]. Here, we speculate that DEX could improve POCD by regulating the balance of Th17/Treg cells, which is associated with the protection of the BBB.

In general, this study may provide evidence of the efficacy and safety of DEX on POCD in elderly orthopaedic patients, and the underlying mechanism may be related to the balance of Th17/Treg cells.

The trial is ongoing and recruiting participants. This study protocol is version 1 made on February 1, 2022. Recruitment commenced in March 2022 at Hebei General Hospital and is expected to be completed in April 2023.