This meta-analysis involved 11 RCTs, aiming to explore the effectiveness of lidocaine infusion in patients undergoing thyroid surgery. Our meta-analysis demonstrated that intravenous infusion of lidocaine during thyroid operation was correlated with lower pain scores in the early postsurgical stage, better quality of recovery on POD 1, reduced opioids consumption during surgery, more stable intraoperative hemodynamics, and reduced incidence of cough during extubation. Besides, we found no lidocaine-related adverse events.
In this meta-analysis, we found that lidocaine infusion during operation could alleviate pain in the early postsurgical period. The potential mechanisms may be as follows: First, voltage-gated sodium channels, an important part of the transmission of peripheral nociceptive stimuli to the center, are inhibited in the presence of lidocaine [37, 38]. Second, lidocaine can inhibit inflammatory cascades reaction within the human body: by inhibiting the activation of the inflammatory cells such as macrophages and neutrophils and decreasing the generation of inflammatory mediators including IL-4, IL-6, and TNF-α [39–41]. Third, lidocaine may act on other target to offer analgesia, such as reducing the production of Nitric oxide (NO), which can exert both anti- and pro-nociceptive effects [42, 43]. The analgesic effect of lidocaine is of great significance, because poor management of postsurgical pain may incur undesirable events: dissatisfaction of patients, postoperative complications, extended hospital stay, and increased inpatient cost [44–47]. However, pain scores in Lido group were similar to Con group at 24h and 48h after surgery (Supplementary Fig. 1). This is because lidocaine has elimination half-time between 90–120 minutes when given intravenously, and can hardly play a role at 24 h after the cessation of administration [48, 49]. However, with the anti-inflammatory feature, we expected lidocaine to offer long-lasting analgesia rather than a short period of pain attenuation found in our meta-analysis. Future studies are needed to resolve this contradiction.
Besides, it is suggested that the minimum clinically important difference was 1.3 on the NRS [50]. Under this criterion, the difference of pain scores at any time point was not clinically significant between two groups. We speculated that, there were well-designed postoperative analgesic regimens in most of included studies (5 out of 6, except for Hu’s study), and the intensity of postoperative pain was limited to a relatively low level. Accordingly, little room was left for lidocaine to exert its analgesic properties. In Hu’s study, methods for postoperative pain management were not mentioned, and differences of VAS scores between two groups were clinically significant (1.5 at 2 h, 1.5 at 4 h, 2.8 at 8 h, 3.4 at 12 h, and 2.1 at 24 h), which in turn supported our speculation.
Pooled results of three studies indicated that lidocaine facilitated recovery on POD 1, which is reasonable because of lower VAS scores in Lido group, and the pain level is an important component of QoR-40 scores [51].
Lidocaine reduced opioids consumption during operation, but not after operation. Various analgesic regimens may explain the high heterogeneity of postoperative opioids consumption.
We also investigated the hemodynamic status at intubating and extubating, during which patients experienced intense nociceptive stimulus and were susceptible to adverse cardiovascular events. From the pooled analysis results, intravenous lidocaine made the hemodynamics more steady. Consequently, elderly patients with cardiovascular and cerebrovascular diseases may benefit greatly from the continuous administration of lidocaine during thyroid surgery. Future studies may examine the potential of lidocaine among these patients.
Unexpectedly, lidocaine slightly prolonged the time to awareness and extubation, and the differences were statistically significant. The potential mechanism may be that, during the recovery period, patients in Lido group experienced less stimulus from the endotracheal tube, drainage, and wound, which enabled them to recover a litter slower from anesthesia, and extubation time was then prolonged.
Emergence cough could be very dangerous for patients undergoing thyroid surgery, leading to wound dehiscence and bleeding. Herein, we found that lidocaine decreased the incidence of cough, parallel with a previous study [52]. The stimulus from the endotracheal tube, suppressed by lidocaine, failed to be transferred to the nervous center and caused cough. Besides, though without statistical significance, lidocaine reduced the incidence of PONV. The intense vagal nerve stimulation during neck surgery may be the main reason for PONV, and lidocaine could inhibit the ascending parasympathetic impulse to the vomiting center by blockade of nerve conduction.
Safety is an essential aspect when lidocaine was administered intravenously. Intravenous lidocaine overdosing may cause cardiovascular (hypotension and bradyarrhythmia) and central nervous (dizziness) symptoms [53, 54]. In our meta-analysis, lidocaine-associated adverse events were not detected. The intravenous lidocaine doses in the included studies were 1-2mg/kg for bolus and 1.5-3mg/kg/h for continuous infusion, where lidocaine plasma concentrations were proved below the toxicity threshold (5ug/ml) [55].
Our meta-analysis has two strengths: On the one hand, to our acknowledgment, it is the first to explore the analgesic effects of perioperative lidocaine infusion in patients undergoing thyroid surgery. Therefore, it offers a novel idea for the multi-model analgesia regimens in thyroid surgery. On the other hand, this meta-analysis was performed based on the 2020 PRISMA statement and the Cochrane Collaboration. Furthermore, we assessed risks of bias for each included study and evaluated the evidence quality according to the GRADE system. Nevertheless, we acknowledge several limitations. First, the number of studies concerning primary outcomes was little, so the underlying publication bias could hardly be evaluated. Second, we only analyzed the pain intensity within 48h after surgery. However, the effect of lidocaine on chronic postsurgical pain (CPSP) after thyroid surgery was seldom investigated, with only one study reported that lidocaine may reduce CPSP. RCTs with large sample size are needed to verify this effect. Third, the small sample size was a universal feature of all 11 included RCTs (n < 120), and most of evidence levels were ranked as “low” and “very low” according to the GRADE scoring system. Consequently, results of this meta-analysis should be interpreted with caution. Fourth, we only paid attention to the comparison between lidocaine and placebo, ignoring the difference of various loading and maintaining doses. Accordingly, the optimal combination of doses remains unknown, which may be addressed in future researches. Finally, the result of pain scores at 8h and 12h altered after sensitivity analysis, further well-designed studies are warranted to validate our findings.