Perioperative multiple low-dose Dexamethasones improves postoperative clinical outcomes after Total knee arthroplasty

Total knee arthroplasty (TKA) has become a successful surgical method for the treatment of severe knee diseases [1–3]. TKA, however, involves extensive osteotomy, soft tissue release and surgical trauma, which often lead to severe postoperative inflammatory reactions [4–6]. Consequently, patients can experience severe pain in the early postoperative period [7, 8], accompanied by postoperative nausea and vomiting (PONV) [9–11], and a prolonged length of stay (LOS) [12]. Pain and PONV may hinder the early recovery of TKA, resulting in patients dissatisfaction [13–16]. Therefore, it is better to improve the fast-track recovery of patients in reducing postoperative inflammation, relieving pain and preventing PONV.

Glucocorticoids, which have powerful anti-inflammatory and antiemetic effects, are widely used in perioperative management, such as abdominal [17, 18], gynaecologic [19], and TKA surgery [20–22], for reducing the postoperative inflammatory response, alleviating postoperative pain and preventing PONV. However, the most suitable protocol for administration and dosage remains controversial. As previously reported, glucocorticoids were given at a single and low dose, with fewer samples in most previous studies [23–25]. In addition, concerns regarding the adverse effects of glucocorticoid therapy, including infection and gastrointestinal bleeding, have potentially limited its widespread use in TKA [26]. Last, although the administration of the drug provides better pain and vomiting relief than traditional methods, many patients still suffer from it at the initial stage after surgery [19, 22, 27].

The current study was therefore designed to compare the effectiveness and safety of multiple low doses of dexamethasone in patients following primary TKA by evaluating: (1) whether multiple low doses of dexamethasone reduce postoperative inflammatory markers and the incidence of PONV; (2) whether multiple low doses of dexamethasone relieve pain and provide an additional analgesic effect, improving the range of motion (ROM) and patient satisfaction; and (3) whether multiple low doses of dexamethasone are safe in primary TKA.

The most important finding of this study is that patients in Group C who were intravenously administered 10 mg dexamethasone 1 h preoperatively and repeated 10 mg at 6 postoperatively can significantly reduce the postoperative level of CRP and IL-6, decrease the incidence of PONV and receive additional analgesic and antiemetic effects, and achieve a better ROM and patient satisfaction, without increasing the risk of wound-related complications when compared with patients in Group A and B.

TKA is one of the most effective methods to treat knee diseases [1, 2]. However, surgical trauma following TKA often results in severe postoperative inflammation, which is associated with postoperative pain and PONV [8, 9]. As a result, the fast-track treatment of the patients was hampered postoperatively. Glucocorticoids are known for their analgesic, anti-inflammatory, and anti-emetic effects, although the mechanisms are unclear. In using corticosteroids, therefore, its pharmaceutical ingredients enter the surrounding tissue and reduce the inflammatory response at the site of surgical trauma, thus providing effective pain relief. Dexamethasone is a kind of synthetic glucocorticoid with high bioavailability and long acting time. In the current study, significant increases in CRP and IL-6 levels were found in the three treatment groups, however, CRP and IL-6 levels increased significantly less in Groups C and B compared with Group A at 24, 48, and 72 h. It was also observed to be lower in Group C than in Group B. Thus, our findings suggest that intravenous dexamethasone administered 1 h preoperatively and repeated at 6 h postoperatively reduced the postoperative inflammatory response compared to Groups A and B.

Compared with the level of pain preoperatively, pain declined after TKA among the three groups. As previously reported, the analgesic effect of glucocorticoid is achieved by inhibiting phospholipase, thus blocking the pathway of cyclooxygenase and lipoxygenase in the inflammatory chain reaction [29]. At the same time, it can also inhibit the level of bradykinin [30] in tissues and the release of neuropeptides from nerve endings [31], both of which may enhance the sense of injury in inflammatory tissues and surgical wounds. An Randomized Controlled Trial (RCT) performed by Koh et al. [22] prospectively evaluated 269 TKAs randomized to receive dexamethasone (10 mg) combined with ramosetron or ramosetron alone. These results suggest that patients with dexamethasone experienced lower pain and consumed fewer opioids during the 6 to 24 h postoperative. Similarly, another RCT study by Xu et al. [32] involving 108 TKA patients divided into 2 groups of 54 patients. The two treatment groups were either given two doses of 10 mg IV dexamethasone or placebo, the study found that the pain at rest and walking was lower at 24 h postoperatively in the dexamethasone group. The results in current study echo those findings. We showed a statistically significant reduction of the VAS score of pain in Group C than Group A at 24 and 48 h postoperatively and Group B at 24 h postoperatively. Furthermore, the requirements of oxycodone and pethidine hydrochloride were significantly lower in Group C.

The antiemetic effects of dexamethasone were well documented [17, 19, 22, 32] and supported in our study. However, the mechanism by which glucocorticoids relieve PONV is not fully understood. Its effect may be mediated by the inhibition of prostaglandin synthesis or the inhibition of endogenous opioid release [33]. The current study showed that two doses of dexamethasone were more effective in preventing the PONV and reducing the intensity of nausea than the single dose or without dexamethasone groups. The results are consistent with previous studies [10, 22, 32] suggesting that dexamethasone has a better antiemetic effect. In a recent meta-analysis of 3 randomized controlled trials [34], dexamethasone not only reduces postoperative pain level and opioid consumption within 48 h but also reduces postoperative PONV. Although few previous studies have investigated the antiemetic efficacy of two doses of low-dose dexamethasone after TKA. The current results as well as previous studies [10, 32] suggest that the use of multiple low doses of dexamethasone has a stronger antiemetic effect on the early stage of PONV than a single dose of dexamethasone. The results therefore suggest that the repeated administration of dexamethasone 6 h postoperatively can effectively reduce the incidence of PONV. Additionally, functional outcome assessments in our study demonstrated a better ROM in Group C. The outcomes might explain the significantly higher satisfaction ratings of patients in Group C at the time of discharge.

However, the optimal routes and doses of dexamethasone remain controversial. A range of doses from 4 to 10 mg in primary TKA has been established in most studies [22, 35]. Barnes et al. [36] suggested that glucocorticoids bind to intracellular glucocorticoid receptors, which are mainly mediated by the synthesis of transcriptional proteins. Therefore, the starting time of biological action is generally 1–2 h [29], and it was reasonable to give dexamethasone 1 h before the surgery so that it reached its plasma concentration at the beginning of resuscitation in this study. In addition, since early media-activated metabolic reaction occurs immediately after surgical incision [37], it is also reasonable to give dexamethasone 1 h before the surgery to obtain a potential therapeutic effect postoperatively. As previously reported [22, 27], patients still have to deal with pain and PONV with single-dose dexamethasone. Thus, we added an additional 10-mg dose of dexamethasone at 6 h postoperatively, assuming that it would have a meaningful clinical benefit.

Although TKA is associated with thrombosis [3, 38], and glucocorticoids are associated with wound healing and postoperative infection, previous studies using low or high doses of glucocorticoids have not shown that glucocorticoids are associated with these complications during the perioperative period [22, 32, 34]. In our study, we also found that the additional low dose of dexamethasone was given at 6 postoperatively, and no patients had an obvious adverse effect and/or complication during postoperative follow-up. It is known that synthetic glucocorticoids,such as dexamethasone, prescribed in daily care can induce hypertension. However, the exact mechanism by which glucocorticoids may induce hypertension is unclear [39]. Some evidence supports the fact that glucocorticoids may actually have nothing to do with elevated blood pressure in the first few weeks. Gabriel et al. [40] reported that 15.3% of 124 patients with rheumatoid polymyalgia prescribed glucocorticoid treatment for hypertension, and 26.3% of 57 patients who received non-steroidal anti-inflammatory drugs had hypertension. Furthermore, Fardet et al. [41] also sugessted that the increase of blood pressure during the first months of exposure to synthetic glucocorticoids seems clinically nonsignificant. At the same time, there was also no evidence that perioperative dexamethasone administration is associated with increased postoperative glucose levels (> 200 mg/dl) or higher maximum glucose levels in total joint arthroplasty [42]. Therefore, we believe that there is evidence to support that two doses of low-dose preoperative treatment with dexamethasone are safe in TKA procedures.

This study had some limitations. The follow-up period for assessing functional outcome was 24 h, 48 h and 72 h postoperatively; therefore, this study does not show the long-term effects of dexamethasone. Second, although this study showed a lower incidence of wound-related complications, a larger sample size is required to adequately assess the significant differences in adverse events. Third, two doses of low-dose dexamethasone showed better clinical results, but the best method and dose of dexamethasone and whether a further use is needed to produce additional results remain unclear.

The administration of 10 mg dexamethasone 1 h before the surgery, and repeated at 6 h postoperatively can significantly reduce the level of postoperative CRP and IL-6 and the incidence of PONV, relieve pain, achieve an additional analgesic effect, and improve the early ROM compared with the other two groups in TKA.