Effects of perioperative intravenous lidocaine infusion for postoperative pain and recovery in elderly patients undergoing surgery: a systematic review and meta-analysis of randomized controlled trials

Background Improving postoperative pain and other potential benefits of IV lidocaine remains a significant debate in elderly patients. This meta-analysis aims to estimate the effect perioperative continuous IV lidocaine in elderly patients undergoing surgery. Method Pubmed/Medline, Web of Science, Embase and CENTRAL through OVID SP were independently searched until November 1, 2019 by two authors. This systematic review and meta-analysis included all randomized controlled trials that compared the effect of continuous IV lidocaine and any placebo or no treatment in aged patients after surgery. Primary outcomes were length of hospital stay and postoperative pain score and second outcomes were postoperative nausea and vomiting, opioid consumption, gastrointestinal recovery and postoperative neuropsychological function status scale. Result Eighteen studies(1175 patients) were included. Meta-analysis suggested that IV lidocaine reduce the postoperative pain scores(visual analogue scale, 0-10cm) at 2h(SMD:-1.30, 95% CI -1.90 to -0.70), 4h(SMD:-1.20, 95% CI -1.91 to -0.49), 6h(SMD:-0.87, 95%CI -1.72 to 0.02), 8h(SMD:-0.84, 95%CI -1.40 to -0.27), 12h(SMD:-0.73, 95%CI -1.14 to -0.32), 24h(SMD:-0.39, 95%CI -0.66 to -0.11), shorten length of hospital stay(MD: -0.30, 95%CI -0.50 to -0.09), decrease the requirement of opioid drugs(SMD: -0.31, 95%CI -0.31 to -0.01) and the incidence of postoperative nausea(OR: 0.52, 95%CI 0.31 to 0.87) in elderly patients undergoing surgery.


Conclusion
The evidence suggested that IV lidocaine significantly reduce postoperative pain intensity and opioid consumption and shorten the length of hospital stay in aged patients. In addition, it was shown that IV lidocaine decrease the requirement of postoperative opioid and incidence of postoperative nausea compared to control group. IV lidocaine maybe a useful assistant during general anesthesia owing to its beneficial effect in several outcomes in geratic patients undergoing surgery.

Background
Postoperative pain management is a major focus after surgery, especially in the field of fast-track surgery, which aims to prevent or reduce common complications including postoperative pain,postoperative nausea and vomiting hypercoagulation deep venous thrombosis, ileus and postoperative cognitive dysfunction and speed up early recovery, in elderly patients [1][2][3][4] .The number of major operations of all over the world annually approaches 250 million [5] with no less than 33 percent of surgical patients over 65 year [6,7] and evidence reveals that postoperative pain and ileus causing extended length of hospital stay are the primary hospitalization expenses driver in the postoperative period [8,9] .Postoperative pain control after surgery in elderly patients has been become a serious clinical problem that many strategies have been applied to decrease postoperative pain and length of hospital stay, containing steroidal anti-inflammation drugs, nonsteroidal anti-inflammatory drug (NSAID) opioid drugs, patient controlled analgesia (PCA) and local anesthesia [10][11][12] . Nevertheless none of them has indicated identical efficacy and opioid medications can caused side effects including nausea and vomiting, megrim, constipation and delay of postoperative early recovery. Recently, some studies have revealed that perioperative continuous intravenous lidocaine infusion improved postoperative outcomes in postoperative pain, consumption of opioid medications and length of hospital stay (LOS) [13][14][15][16] . However, its effect on postoperative outcomes is not well identified due to their small sample and the deficiency of multicenter and large sample randomized controlled trials. Therefore, this review aimed to systematically assessed the effect of perioperative continuous intravenous lidocaine infusion in elderly patients undergoing surgery, in terms of postoperative pain control, postoperative opioid consumption, length of hospital stay, gastrointestinal (GI) recovery, opioid related adverse events such as postoperative nausea and vomiting (PONV) and postoperative neuropsychological function status scale.

Protocol and registration
The protocol of this review was registered with the International Prospective Register of Systematic Reviews (PROSPERO) before we started to search. Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA) statement [17] was followed in conducting and reporting this systematic review and meta-analysis by us (http://www.prisma-statement.org).

Eligibility criteria
All randomized controlled trials (RCTs) studies included were that evaluated the effect of perioperative lidocaine continuous intravenous infusion comparing with placebo, saline or blank control on at least one of relevant outcome of our interest. The intravenous lidocaine infusion must have been started preoperatively or intraoperatively (with or without an intravenous bolus) and continued until the end of surgery or a period of postoperation.

Searched database resource
Two authors independently searched electronic database Pubmed/Medline, Web of Science, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) through Ovid SP from the time of database construction to 10 November, 2019. A subject-specific search strategy was developed using in Pubmed/Medline and applied that as the basic of the search strategies in the other electronic databases. We also scanned the reference lists and citations of included trials and any relevant systematic reviews referred to further literatures to additional trials. If necessary, we contacted trial authors to achieve additional information. We did not apply any restrictions to language and the type of surgery when searching. The literature search strategy was provided in additional file: appendix 1.

Study selection
We included the study which conformed to the following criterias: 1.Randomized controlled study (RCT) 2.Patients' age ≥60 years old 3.Undergoing surgery whether selective operation or emergency operation 4.Perioperative continuous intravenous lidocaine infusion 5.At least containing one of the outcomes of our interest and whose relative data can be exacted Two authors respectively scanned the title and abstract of identified records to exclude uncorrelated studies and accessed the full-text articles for eligibility. We resolved any disagreements in each step by discussion or consulting the arbiter.

Data extraction
Two authors independently exacted the data of all of the included studies using standard data exaction form prepared by authors, which contained the first author, published year, study design, surgery type, population characteristics, details of lidocaine infusion and reported outcomes of our interest. If necessary, we contacted the authors of included studies by email to achieve the additional data that were missing in published. If additional information was not received, we exacted data and information from the figures. At each step of exacting data, we resolved any divergences by discussion or consulting arbiter.

1.Postoperative pain intensity
Pain score at rest, cough and movement (0 to10cm, 0 to 100mm visual analogue scale

Risk of bias in individual studies
Two authors respectively assessed the risk of bias of all included studies. The Cochrane risk of bias tool was used to assess the risk of bias of included studies and each component was judged as low risk of bias (green), high risk of bias (red) or unclear risk of bias (yellow) and the result was shown in Fig. 2.

Summary measures and synthesis of results
For the outcome of the post-operation opioid consumption, all various opioid qualities was converted to intravenous morphine equivalent (MEQ, mg) to describe the consumption of opioid (http://www.whocc.no/atc_ddd_index).
For outcome PONV, we respectively assessed two outcomes: When the mean and standard difference (SD) were not reported and were not obtained by contacting the relevant authors as soon as possible, they were calculated by using the median and standard error (SE) or confidence interval (CI), or the interquartile rang (IQR) if the data distribution was symmetrical [18] . For continuous data, if studies measured data on the same way and scale, the mean difference (MD) was obtained from the difference between experimental group and control group with mean values and SD and if studies assessed the same outcome but measured it with different scales or ways, the standardized mean difference (SMD) was used.
For dichotomous outcomes, the odds ratio (OR) was assessed from experimental and control group event rates and 95%CI was calculated.
Random effect model was use to analysis the combined data which was assumed that clinical heterogeneity existed. The I 2 statistics was used to report the heterogeneity, which was classified by applying Cochrane Handbook of Systematic Reviews of Interventions and when I 2 >50%, it was considered the existence of obvious heterogeneity.
Further, if I 2 >50%, a several subgroup analyses and sensitivity analysis were conducted to evaluate the source of heterogeneity and to assess the subpopulation of patients that could probably obtain benefits from the intervention. Subgroup analysis was performed in outcomes of length of hospital stay grouped by the type of surgery and sensitivity analysis was performed in postoperative pain score. Funnel plots were used to check the publication bias.

Search result
We present the results of literature search in a PRISMA flow chart (Fig. 1). 3789 records were identified through database searching. After duplicating, screening the initial title and abastract,81 full texts were retrieved for comprehensive evaluation. Finally, 18 RCTs were included which contained 1175 patients met the inclusion criteria in the present meta-analysis included in the final analyses.

Study characterizes
The patients of these 18 RCTs whose average age older than 60. These articles contained 595 patients in lidocaine groups and 580 patients who received normal saline or nothing served as control. Studies were carried through in patients undergoing abdominal, cardiac, orthopedic, urinary, endoscopic surgery. Nine of the studies reported surgery time, and all studies mentioned duration of infusion. A lidocaine bolus (1-2mg/kg) was given before surgical incision in 17 of the 18 RCTs whereas all eligible RCTs followed by a continuous infusion during and after operation. The characteristics of the included trials were summarized in Table 1.

Risk of bias within studies
We evaluated the quality of the included RCTs on the basis of the Cochrane Handbook of Systematic Reviews of Interventions, version 5.1.0 (updated March 2011) [18] .The entire risk of bias concerning selection bias, performance bias, attrition bias, detection bias and other bias exposed low risk of bias in more than 65% across all included all studies ( Fig. 2 and Fig. 3).

Postoperative pain
Postoperative pain was evaluated by different pain scores. The pain scores were provided in totally 11 studies of 18 RCTs which had sufficient quantitative data to be combined through meta-analysis [19][20][21][22][23][24][25][26][27][28][29] .Five studies assessed postoperative pain on a visual analogue scale (VAS) from 0 to 100mm and five studies used the VAS from 0 to 10cm measurement, while one trial evaluated postoperative pain with NRS.
We performed the robust of the evidence by sensitivity analysis, The difference of the combined effect was detected by different effect model. The estimated effect(95%CI) for the sensitivity analysis remained robust about the pain scores at different point times from 2h to 48h after surgery when selecting random effect model or fixed effect model, which showed that the results were reliable.

Gastrointestinal recovery
Six studies [20,25,29,30,33,35] with 285 patients reported data on the time to first flatus and the time to first defaecation/bowel movement.

Time to first flatus
The combined analysis did not demonstrate a significant reduction of time to flatus in lidocaine group compared with the control group (MD -3.24 95%CI -9.90 to 3.41).

Time to first defaecation/bowel movement
There was enough evidence of effect for lidocaine infusion in contrast with the control group to shorten the time to first defaecation/bowel movement (MD -8.64 95%CI -16.00 to -1.28).

Postoperative neuropsychological function status scale
Only one studies [34] proved lidocaine administration during and after surgery does not reduce the high rate of postoperative cognitive dysfunction.

Adverse events
The complication of nausea was reported in 9 trials [19, 21, 22, 27-29, 33, 35, 36] ,whereas three articles [19,21,28] showed the complication of vomiting. It illustrated respectively that there was significant reduction in nausea in lidocaine group contrasted with control group (n=479 OR 0.56 95%CI 0.37 to 0.84). There was no statistical difference about vomiting between lidocaine group and control group (n=120 OR 0.47 95%CI 0.19 to 1.1) but there was a slightly lower incidence of vomiting in lidocaine group when compared with the control group.

Risk of bias across studies
The funnel plot was used to investigated the risk of bias across studies (publication bias).
For outcome of postoperative pain, the funnel plot at 24h after surgery suggested funnel plot asymmetry on visual inspection, publication bias was likely to be present (Fig. 5). The funnel plot for the duration of hospital stay suggested funnel plot was symmetrical on visual inspection, indicating that publication bias was not likely to be present (Fig. 8).

Additional analysis
Additional analyses such as subgroup analysis, sensitivity analysis and publication bias analysis were performed to evaluate which surgery may benefit from IV lidocaine administration (subgroup analysis), the robust of result in terms of risk of bias from single study (sensitivity analysis) and the appearance of risk of bias across analysis (publication bias). By this means we researched the primary outcome, such as subgroup analysis for length of hospital stay, sensitivity analysis for postoperative pain at 24h after surgery and publication bias analysis for length of hospital stay and postoperative pain at 24h after surgery. 1.
Subgroup analysis. The preplanned subgroups analysis on type of surgery accounted for heterogeneity about all subgroups (Fig. 7 Nevertheless, there is no statistical significance in postoperative vomiting between IV lidocaine group and control group. In addition, there was less requirement of opioid consumption in IV lidocaine group compared to placebo or no treatment of control group and there was a lower risk of postoperative nausea, which is related to opioid using to some extent.
The mechanism of potential analgesia effect and other potential benefits of IV lidocaine remains unclear [39] . Two explanations that were selective suppression of pain transfer in spinal marrow and blocking the sodium channel of mechanosensitive nociceptor have been reported to interpret the mechanism of reduction pain of IV lidocaine. In addition, IV lidocaine has also revealed anti-inflammatory benefits [40] .Previous studies have demonstrated that IV lidocaine reduced the level of inflammatory mediators [41] .
Therefore, the mechanism that IV lidocaine reduce postoperative pain require more animal experiments and clinical trials to provide a stronger evidence. In our review, the length of hospital stay of IV lidocaine compared to control group was statistical difference, however, the heterogenicity was large, which was contrast to some articles and meta-analyses [9,  And what we mentioned above may be the one resource of the heterogeneous in this review.
Thirdly, the heterogeneous outcome published was also a limitation. Although subgroup and sensitivity analysis was performed to make it lower, however, not all planned subgroup and sensitivity analysis could be carry out due to insufficient data reported.
Thus, the heterogeneity could not always be explicated. At last, the range of published year of all included studies was large, which was from 1995 to 2019. There was no funding support.

Ethics approval and consent to participate
Not applicable.

Consent for publication
Not applicable.

Availability of data and materials
The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

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

Funding
This review did not receive any specific grant from funding agencies.

Authors' contributions
YHZ and FW have contributed equally to this review. Any disagreements was resolved by consulting LY and TZ and they revised the manuscript critically. All authors read and approved the final manuscript.       The forest plot for pain score at rest between lidocaine and control groups by time points Figure 5 The funnel plot for pain score of 24h at rest between lidocaine and control groups The forest plot for pain score at movement between lidocaine and control groups by difference time points The forest plot for length of hospital stay outcome between lidocaine and control groups by type of surgery