Ketamine Supplementation To Bupivacaine For Knee Arthroscopy: A Meta-Analysis of Randomized Controlled Trials

Introduction: The ecacy of ketamine supplementation to bupivacaine for pain management of knee arthroscopy remains controversial. We conduct a systematic review and meta-analysis to explore the inuence of ketamine supplementation to bupivacaine on the postoperative pain intensity of knee arthroscopy. Methods: We have searched PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through July 2021 for randomized controlled trials (RCTs) assessing the effect of ketamine supplementation to bupivacaine on pain control of knee arthroscopy. This meta-analysis is performed using the random-effect model. Results: Four RCTs are included in the meta-analysis. Overall, compared with control group for knee arthroscopy, ketamine supplementation remarkably decreases pain scores at 30 min (SMD=-0.98; 95% CI=-1.42 to -0.55; P<0.00001) and number of additional analgesics (OR=0.27; 95% CI=0.10 to 0.71; P=0.008), but reveals no signicant impact on pain scores at 1 h (SMD=-1.34; 95% CI=-3.42 to 0.73; P=0.20), pain scores at 6 h (SMD=-0.33; 95% CI=-1.39 to 0.72; P=0.53), time of rst analgesic requirement (SMD=1.27; 95% CI=-0.95 to 3.49; P=0.26) or additional analgesic consumption (SMD=-2.25; 95% CI=-5.89 to 1.40; P=0.23). Conclusions: Ketamine supplementation may improve the pain control when in combination with bupivacaine for knee arthroscopy.


Introduction
Arthroscopic knee surgery has been widely used in orthopedic surgeries [1][2][3][4]. Postoperative pan of knee arthroscopy commonly occurs due to stimulating the bare nerve endpoints and afferent nociceptors, releasing in ammatory mediators such as bradykinin, serotonin and histamine from injured cells [5,6].
Insu cient pain control may result in prolonged hospital stay and delayed discharge [7][8][9]. Various analgesia methods has been developed to target the routes of nerves and various neurotransmitters to inhibit hyperalgesia and nociception, which may improve in ammatory and neurogenic conditions [10,11].
Ketamine shows important analgesic effect in systemic and peripheral use through interacting with a large number of receptors such as opioid, muscarinic, and N-methyl-D-aspartate (NMDA) receptors, and NMDA receptors display a signi cant role in peripheral somatic and visceral pain pathways [12]. In instance, NMDA receptors exist in the knee joint of the rats, and intraarticular administration of ketamine provides adequate analgesia for arthritic joints [13]. Bupivacaine has been widely used for analgesia, and addition of ketamine to bupivacaine for wound in ltration is documented to prolong the analgesic duration and increase the pain threshold [14].
The addition ketamine to bupivacaine for the pain management of knee arthroscopy has not been well established, and several studies reported the con icting results [15][16][17]. With accumulating evidence, we therefore perform a systematic review and meta-analysis of RCTs to explore the e cacy and safety of ketamine supplementation to bupivacaine in patients with knee arthroscopy.

Materials And Methods
Ethical approval and patient consent are not required because this is a systematic review and meta-analysis of previously published studies. The systematic review and meta-analysis are conducted and reported in adherence to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) [18,19].

Search strategy and study selection
Two investigators have independently searched the following databases (inception to July 2021): PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases. The electronic search strategy is conducted using the following keywords: ketamine, bupivacaine and knee arthroscopy. We also check the reference lists of the screened full-text studies to identify other potentially eligible trials.
The inclusive selection criteria are as follows: (i) study design is RCT; (ii) population are patients undergo knee arthroscopy; (iii) intervention treatments are ketamine plus bupivacaine versus bupivacaine.

Data extraction and outcome measures
We have extracted the following information: author, number of patients, age, female, body weight, duration of surgery and detail methods in each group etc.
Data have been extracted independently by two investigators, and discrepancies are resolved by consensus. We also contact the corresponding author to obtain the data when necessary.
The primary outcomes are pain scores at 30 min and number of additional analgesics. Secondary outcomes include pain scores at 1 h, pain scores at 6 h, time of rst analgesic requirement, and additional analgesic consumption.

Quality assessment in individual studies
Methodological quality of the included studies is independently evaluated using the modi ed Jadad scale [20]. There are 3 items for Jadad scale: randomization (0-2 points), blinding (0-2 points), dropouts and withdrawals (0-1 points). The score of Jadad Scale varies from 0 to 5 points. An article with Jadad score≤2 is considered to be of low quality. If the Jadad score≥3, the study is thought to be of high quality [21].

Statistical analysis
We estimate the standard mean difference (SMD) with 95% con dence interval (CI) for continuous outcomes (pain scores at 30 min, pain scores at 1 h, pain scores at 6 h, time of rst analgesic requirement and additional analgesic consumption) and odd ratio (OR) with 95% CIs for dichotomous outcomes (number of additional analgesics). The random-effects model is used regardless of heterogeneity. Heterogeneity is reported using the I 2 statistic, and I 2 > 50% indicates signi cant heterogeneity [19,22]. Whenever signi cant heterogeneity is present, we search for potential sources of heterogeneity via omitting one study in turn for the meta-analysis or performing subgroup analysis. All statistical analyses are performed using Review Manager Version 5.3 (The Cochrane Collaboration, Software Update, Oxford, UK).

Results
Literature search, study characteristics and quality assessment A detailed owchart of the search and selection results is shown in Fig. 1. 132 potentially relevant articles are identi ed initially. Finally, four RCTs that meet our inclusion criteria are included in the meta-analysis [15][16][17]23].
The baseline characteristics of the four eligible RCTs in the meta-analysis are summarized in Table 1. The three studies are published between 2001 and 2020, and total sample size is 172. Among the four studies included here, two studies report pain scores at 30 min [17,23], two studies report number of additional analgesics [15,23], three studies report pain scores at 1 h [16,17,23], two studies report pain scores at 6 h [17,23], three studies report time of rst analgesic requirement [15][16][17], and two studies report additional analgesic consumption [17,23]. Jadad scores of the four included studies vary from 3 to 5, and all four studies are considered to be high-quality ones according to quality assessment. These outcome data are analyzed with the random-effects model, and compared to control group for knee arthroscopy, ketamine supplementation is associated with signi cantly reduced pain scores at 30 min (SMD=-0.98; 95% CI=-1.42 to -0.55; P < 0.00001) with no heterogeneity among the studies (I 2 = 0%, heterogeneity P = 0.92) (Fig. 2) and number of additional analgesics (OR = 0.27; 95% CI = 0.10 to 0.71; P = 0.008) with no heterogeneity among the studies (I 2 = 0%, heterogeneity P = 0.87) (Fig. 3).

Sensitivity analysis
No heterogeneity is observed for these outcomes and thus we do not perform sensitivity analysis via omitting one study in turn to detect the heterogeneity.

Discussion
Knee arthroscopic surgery can result in moderate to severe pain because of the insertion of arthroscopic instruments into the joint, bone removal, soft tissue dissection and distention [24][25][26][27][28]. One study compared the analgesic effect of tramadol, magnesium, and ketamine after arthroscopic meniscectomy, and unraveled that 1 mg/kg intraarticular ketamine reduced additional analgesic requirement and facilitated early mobilization [29]. In addition, 0.5 mg/kg ketamine was documented to improve the analgesic e cacy of both tramadol and ropivacaine on pain management after arthroscopic meniscectomy [30].
However, supplementation with ketamine to bupivacaine reported con icting results for the analgesia of knee arthroscopy [16,17,23]. Our meta-analysis has included four RCTs and 172 patients. The results reveals that ketamine supplementation to bupivacaine can signi cantly reduce the pain scores at 30 min and number of additional analgesics after knee arthroscopy, but showed no obvious impact on pain scores at 1 h, pain scores at 6 h, time of rst analgesic requirement or additional analgesic consumption. In addition, one RCT reported the similar incidence of adverse events such as postoperative nausea and vomiting, urinary retention and pruritus [15].
Considering the sensitivity analysis, although there is no signi cant heterogeneity, several factors may result in some bias. Firstly, different administration routes are included, such as intraarticular [15,17] and intravenous [16,23] approaches. Secondly, the doses of ketamine range from 0.15 mg/kg to 1.0 mg/kg, which may affect the e cacy assessment. Thirdly, various operation procedures during knee arthroscopy are associated with different pain intensity, and may have some impact on the analgesia of ketamine supplementation.
This meta-analysis has several potential limitations. Firstly, our analysis is based on four RCTs, and all of them have a relatively small sample size (n < 100).
Overestimation of the treatment effect is more likely in smaller trials compared with larger samples. Next, although there is no signi cant heterogeneity, different administration routes and doses of ketamine supplementation may produce some bias. Finally, it is not feasible to perform the meta-analysis of some important index such as pain scores at longer follow up time and perform the subgroup analysis based on dosages due to the limited studies.

Conclusions
Ketamine supplementation to bupivacaine may be effective to improve the analgesia of knee arthroscopy.

Declarations
Ethics approval and consent to participate Not applicable.

Consent for publication
Not applicable.

Competing interests
The authors declare that they have no competing interests.

Funding
Not applicable. Flow diagram of study searching and selection process.

Figure 2
Forest plot for the meta-analysis of pain scores at 30 min. Forest plot for the meta-analysis of number of additional analgesics. Forest plot for the meta-analysis of pain scores at 1 h.

Figure 5
Forest plot for the meta-analysis of pain scores at 6 h.

Figure 6
Forest plot for the meta-analysis of time of rst analgesic requirement.

Figure 7
Forest plot for the meta-analysis of additional analgesic consumption.