Combining ropivacaine transversus abdominis plane block with intravenous lidocaine infusion in adults undergoing colorectal cancer surgery: an open-label, dose-escalation exploratory trial

Combining ropivacaine transversus abdominis plane block with intravenous lidocaine infusion in adults undergoing colorectal cancer surgery: an open-label, dose-escalation exploratory trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Combining ropivacaine transversus abdominis plane block with intravenous lidocaine infusion in adults undergoing colorectal cancer surgery: an open-label, dose-escalation exploratory trial Mengmeng Zhou, Feng Yu, Yan Xu, Jingwen Wu, Lajing Luowu, Qianqian Tang, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5690114/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 Jul, 2025 Read the published version in BMC Anesthesiology → Version 1 posted 5 You are reading this latest preprint version Abstract Background The concurrent use of a ropivacaine transversus abdominis plane (TAP) block with intravenous lidocaine infusion, though effective for pain relief, raises safety concerns regarding local anesthetic systemic toxicity (LAST). This study aimed to assess the dose-risk relationship of LAST in this combination by escalating the ropivacaine dose while fixing the lidocaine dose. Methods In this dose-escalation study, adult patients undergoing colorectal cancer surgery received a 0.2% ropivacaine TAP block (1.5, 2.0 or 2.5 mg kg − 1 ) and intravenous lidocaine infusion (2 mg kg − 1 bolus, followed by 2 mg kg − 1 h − 1 ), both dosed according to ideal body weight (IBW). The primary outcome was the occurrence of LAST, identified by clinical symptoms, new-onset ECG irregularities, etc. Secondary outcomes included plasma concentrations of ropivacaine and lidocaine. Results Nine patients were included in the per-protocol analysis, and 26 were included in the intention-to-treat analysis. No signs of LAST were observed. Plasma ropivacaine concentrations remained consistently below 2.2 µg mL − 1 , however, eight patients in the intention-to-treat population and three patients in the per-protocol population had plasma lidocaine concentrations exceeding 5.0 µg mL − 1 at 10 minutes post-bolus. In the per-protocol population, peak plasma ropivacaine concentrations occurred 30 minutes (range, 20–60) post-TAP block, with median values of 1.14 (range, 0.85–1.18), 1.42 (range, 1.29–1.80), and 1.96 (range, 1.47–2.06) µg mL − 1 across dose groups. The peak plasma lidocaine concentrations in patients occurred at 10 minutes post-bolus infusion, with median values of 4.59 µg mL − 1 (range, 3.24–6.67) and gradually decreased after 2 hours. The intention-to-treat analysis found similar results. Conclusion Although no signs of LAST were observed with the combination of a 1.5 to 2.5 mg kg − 1 ropivacaine TAP block and intravenous lidocaine infusion under general anaesthesia, extreme caution is still warranted regarding the potential risk of LAST. Figures Figure 1 Figure 2 Figure 3 Introduction Postoperative pain severely impairs early mobility and increases the risk of postoperative complications, causing prolonged hospital stays and delayed recovery [ 1 ]. Despite advancements in pain management, achieving optimal postoperative analgesia remains a challenge [ 2 ]. In colorectal cancer surgery, postoperative pain, especially movement-evoked pain, affects over 50% of patients, highlighting the urgent need for effective pain management strategies [ 3 ]. Multimodal analgesia protocols have become increasingly prevalent in clinical practice to address these challenges [ 4 ]. Among these approaches, the transversus abdominis plane (TAP) block, which provides extensive pain relief by targeting a broad range of sensory nerves [ 5 – 7 ], and intravenous lidocaine, commonly used perioperatively for its anti-hyperalgesic and anti-inflammatory properties, have both demonstrated significant efficacy in pain relief and opioids reduction [ 8 ], particularly in colorectal surgery [ 9 ]. Our previous study indicated that combining intravenous lidocaine with local wound infiltration using ropivacaine provided superior pain relief compared to ropivacaine infiltration alone [ 8 ]. However, this combination also raises significant safety concerns, particularly regarding the risk of local anesthetic systemic toxicity (LAST) [ 10 ]. Despite these safety concerns, a survey of anesthetists in Australian and New Zealand revealed that over 25% of respondents utilized both analgesia protocols in surgical patients [ 11 ]. Although international consensus guideline recommends a 4-hour interval between the administration of these local anesthetics to minimize this risk [ 10 ], adherence to these guidelines in clinical practice remains suboptimal. Reports indicated that only 37% of anaesthesiologists discontinued lidocaine infusion before performing a local block, while 44% merely reduced the local anesthetic dose instead [ 11 ]. This discrepancy between recommended guidelines and actual clinical practice highlights a significant gap, underscoring the need for further investigation into the potential LAST risk when the two local anesthetics are combined and administered across multiple routes. Given that the effective dosage range for ropivacaine in TAP blocks is reported to be 1.5 mg kg − 1 to 2.5 mg kg − 1 [ 12 , 13 ], and intravenous lidocaine is typically administered as a bolus dose of 1.5-2 mg kg − 1 followed by a continuous infusion at 1.5-2 mg kg − 1 h − 1 [ 8 , 9 , 14 ], our study will fix the lidocaine infusion dose and initiate ropivacaine at lower doses for TAP blocks using a dose-escalation strategy to assess the dose-risk relationship. Methods Ethics statements This trial was registered prospectively with ClinicalTrials.gov (NCT06006026, principal investigator: Chunling Jiang, date of registration: August 23, 2023). Ethical approval was obtained from the Ethics Committee of West China Hospital, Sichuan University (approval number HX20201180-1). All patients provided informed consent and were enrolled after registration. Study design This open-label, dose-escalation trial followed a 3 + 3 model to assess whether escalating doses of ropivacaine, as observed in previous studies [ 12 , 13 ], when combined with a fixed intravenous dose of lidocaine [ 15 ], increased the risk of LAST. The trial was conducted at the West China Hospital of Sichuan University from August 28, 2023, to May 15, 2024. The 3 + 3 dose-escalation model, commonly employed in Phase I trials, was selected in this study due to the uncertainty surrounding the toxicity of combining the two local anesthetics. This approach minimized risk by limiting exposure. The sample size was determined by the number of dose levels tested, with additional patients being included only if necessary to replace incomplete data sets or to further assess potential adverse events. Patient recruitment We included patients aged 18–65 years with an American Society of Anaesthesiologists (ASA) physical status of I–II, who were scheduled for elective colorectal surgery. The exclusion criteria were body weight 100 kg, cardiac rhythm disorders or systolic heart failure (including second- and third-degree heart block and ejection fraction < 50%), severe liver dysfunction (alanine aminotransferase, aspartate aminotransferase, or bilirubin levels 2.5 times higher than normal), severe renal dysfunction (creatinine clearance rate < 60 mL/min), contraindications to lidocaine or ropivacaine, and communication difficulties. Anaesthesia management Upon arrival at the operating room, patients were monitored with electrocardiography (ECG), blood oxygen saturation, blood pressure monitoring, and electroencephalography (EEG). General anaesthesia was induced with midazolam (2 mg), propofol (1.5–2.5 mg kg − 1 ), sufentanil (0.2–0.3 µg kg − 1 ), and cisatracurium (0.2 mg kg − 1 ). After tracheal intubation, anaesthesia was maintained with remifentanil (0.1–0.2 µg kg − 1 min − 1 ) and desflurane or sevoflurane in a mixture of 40% air and 60% oxygen to maintain the Patient State Index (PSI) within a range of 25–50, as monitored by the Masimo Root monitor [ 16 ]. After surgery, all patients were extubated in the operating room and transferred to the post-anaesthesia care unit (PACU), where they were monitored according to the institutional PACU protocol [ 8 ]. Study intervention After anaesthesia induction, an experienced anaesthesiologist performed bilateral TAP blocks using high-frequency linear array ultrasound probes (AnaesusME7 Mindray Bio; Medical Electronics, Shenzhen, China). Success of the TAP block was confirmed using the technique described by Griffiths and colleagues[ 13 ] (Supplementary Figure S1 ). TAP blocks were administered using a dose-escalation approach based on ideal body weight (IBW, IBW = 45.4 + 0.89ⅹ(height–152.4) (+ 4.5 if male)[ 17 ], initiating with the lowest dose for three initial patients. Concurrently, patients received an intravenous infusion of lidocaine at a dose of 2.0 mg kg − 1 over a duration of 10 minutes, followed by a continuous infusion at 2.0 mg kg − 1 h − 1 until the end of surgery. Doses were also calculated based on IBW. If no signs of LAST were observed, an additional three patients were recruited at the next higher dose. Notably, if blood samples could not be obtained for measurement of the plasma concentrations, new patients were enrolled until at least three patients per dosage group had complete blood sample data. In the event of an adverse event related to LAST, three additional patients were enrolled at the same dose level (Fig. 1 ). The initial dose selection was based on previous studies confirming its safety and efficacy [ 12 ]. The dose at which no more than one of the three patients experienced an adverse event related to LAST was designated as the recommended phase 2 dose. Three dose levels were evaluated: 1.5 mg kg − 1 , 2.0 mg kg − 1 , and 2.5 mg kg − 1 of 0.2% ropivacaine. Further dose escalation beyond 2.5 mg kg − 1 was not pursued due to potential neurotoxicity reported with 3.0 mg kg − 1 [ 18 ]. Adverse event management In the event that patients experienced severe signs of LAST, characterised by generalised seizures, life-threatening arrhythmia or unexplained loss of consciousness, local anaesthetics were discontinued immediately and a 20% lipid emulsion was administered [ 19 ]. Adverse events and their treatments were meticulously documented. Study outcomes The primary outcome was the occurrence of LAST, identified by clinical symptoms such as dizziness, light-headedness, metallic taste, perioral numbness, tinnitus, seizures, unexplained loss of consciousness, or new-onset ECG irregularities [ 19 ], occurring from the administration of local anesthetics up to 24 hours postoperatively. Intraoperative EEG abnormalities, such as continuous or recurrent focal or generalized spikes, sharp waves, or rhythmic theta or delta activity, were also considered as indicators of LAST [ 20 – 22 ]. Secondary outcomes included plasma concentrations of ropivacaine and lidocaine at various time points (10, 20, 30, 45, 60, and 90 minutes and 2, 4, 6, 12, and 24 hours) following the completion of bilateral TAP blocks and the initiation of intravenous lidocaine infusion. Data collection Blood samples were obtained from the contralateral side of the lidocaine infusion site. Samples were processed for serum storage and batch analysis using high-performance liquid chromatography with carbamazepine as the internal standard [ 23 ]. Intraoperative adverse events, including new-onset ECG irregularities or EEG abnormalities, such as continuous or recurrent focal or generalized spikes, sharp waves, or rhythmic theta or delta activity [ 20 – 22 ], were assessed by an experienced anaesthesiologist trained in ECG and EEG. After extubation, adverse events, including signs, or ECG changes related to LAST [ 19 , 24 ], were assessed and monitored by trained assessors at the bedside for up to 24 hours postoperatively. All EEG recordings were ultimately evaluated by a neurologist to confirm again. Additionally, postoperative analgesic consumption during 24 hours was recorded and converted into intravenous morphine equivalents (mg) using the Practical Pain Management calculator ( https://opioidcalculator.practicalpainmanagement.com/ ), with the NRS score also documented at 24 hours postoperatively. Statistical analysis Sample size estimation This study followed a 3 + 3 design, with the final sample size depending on real-time response of the patients at each dose level. The maximum sample size was typically six times the number of dose levels, with complete blood samples at each time point [ 25 ]. General statistical analysis Results of descriptive analysis of normally distributed variables were presented as mean and standard deviation (SD), whereas non-normally distributed data were presented as median (interquartile range, IQR) or median (range). Categorical variables were presented as the number of cases (percentage). Primary analyses were based on the per-protocol (PP) population, and secondary sensitivity analyses were done on the intention-to-treat (ITT) population for the primary and secondary outcomes. The normality of data distribution was assessed by evaluating histograms and using the Shapiro–Wilk test to determine the appropriate comparison tests (parametric versus nonparametric). Statistical analysis was performed using SPSS software (version 22.0; IBM Corp.). Results During the study, 45 patients were screened for eligibility. Of these, 26 were involved and treated with a combination of a ropivacaine TAP block and lidocaine intravenous infusion according to their assigned dose (Supplementary Figure S2 ). Blood samples were missed at certain time points for 17 patients. Consequently, the PP analysis included 9 patients. The patient enrollment process is illustrated in the Consolidated Standards of Reporting Trials (CONSORT) flow diagram shown in Fig. 2 . PP, per-protocol; ITT, intention-to-treat. The characteristics of the enrolled patients are summarized in Table 1 . The median age of the patients was 57 years (IQR: 48–61), with 13 (50%) being male and body mass index (BMI) 23.6 kg m − 2 (IQR: 22.5–25.8). The duration of anaesthesia was 3.9 hours (IQR: 3.3–4.3). The median doses of lidocaine and ropivacaine administered during anaesthesia were 456 mg (IQR: 403–528) and 100 mg (IQR: 85–136), respectively. Intraoperative hemodynamic changes over times were presented in Supplementary Table 1. Postoperative morphine equivalent consumption during 24 hours and the NRS score at 24 hours were also provided in Table 1 . Table 1 Baseline characteristic and perioperative data of all patients. 1.5 mg kg − 1 group n = 10 2.0mg kg − 1 group n = 8 2.5mg kg − 1 group n = 8 All n = 26 Baseline characteristic Age (y) 58(52–64) 58(47–64) 50(47–58) 57(48–61) Sex (male, n [%]) 5(50.0%) 3(37.5%) 5(62.5%) 13(50.0%) Height (cm) 161(152–168) 159(155–167) 167(160–170) 162(157–168) Weight (kg) 58(53–67) 60(54–73) 69(62–73) 61(55–71) BMI (kg m − 2 ) 22.8(22.3–24.4) 24.2(22.1–25.8) 24.5(22.9–27.0) 23.6(22.5–25.8) Baseline BP (mmHg) SBP 123(119–142) 121(112–138) 122(114–140) 122(118–140) DBP 76(67–88) 73(66–81) 76(66–83) 75(67–84) HR (beats/min) 73(61–79) 66(56–87) 70(63–75) 71(62–77) ASA physical status 2 (n, [%]) 9(90.0%) 7(87.5%) 8(100.0%) 24(92.3%) 3 (n, [%]) 1(10.0%) 1(12.5%) 0(0.0%) 2(7.7%) Preoperative chemotherapy (n, [%]) 4(40.0%) 1(12.5%) 1(12.5%) 6(23.1%) Preoperative test Hb (g L − 1 ) 128(117–132) 117(102–132) 110(102–119) 118(105–131) ALT (IU L − 1 ) 19(11–34) 16(9–23) 12(8–31) 16(10–29) AST (IU L − 1 ) 23(14–34) 20(15–21) 17(15–29) 19(14–31) Alb (g L − 1 ) 40(37–42) 40(38–42) 42(42–43) 41(38–42) Cre (mmol L − 1 ) 70(57–75) 62(56–69) 84(62–90) 68(58–84) Intraoperative data Ropivacaine dose (mg) 83(67–93) 102(95–126) 157(131–164) 100(85–136) Lidocaine bolus dose (mg) 111(89–124) 102(95–126) 126(105–131) 111(98–128) Lidocaine total dose (mg) 446(367–483) 487(426–623) 477(378–551) 456(403–528) Remifentanil dose (mg) 1.5(1.1–1.6) 1.6(1.0-1.9) 1.2(0.9–1.7) 1.4(1.0-1.7) Sufentanil dose (µg) 27.5(20-32.5) 27.5(25–30) 27.5(23.1–34.4) 27.5(24.4–32.5) Anaesthesia duration (h) 3.9(3.1–4.2) 4.4(4.0-4.8) 3.3(3.2–3.8) 3.9(3.3–4.3) Surgery duration (h) 2.6(2.0–3.0) 2.8(2.5–3.4) 2.3(2.1–2.8) 2.6(2.2-3.0) Fluid infusion (ml) 1450(1200–1625) 1850(1450–2300) 1300(1225–1888) 1525(1300–1700) Blood loss (ml) 20(20–30) 20(20–28) 25(20–48) 20(20–30) Urine output (ml) 200(138–325) 375(263–675) 175(113–300) 275(150–400) Postoperative 24 hours Morphine equivalent (mg) 36.8 ± 12.0 37.8 ± 11.3 35.5 ± 11.5 36.7 ± 11.6 NRS score at rest 1.4 (0.8) 1.5 (0.5) 1.4 (0.4) 1.4(0.6) NRS score during movement 3.6 (0.5) 3.6 (0.8) 3.2 (0.6) 3.5(0.6) Data are presented as absolute number (%), median (interquartile range); M, male; F, female; BMI, body mass index; BP, blood pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; Hb, haemoglobin; AST, aspartate aminotransferase; ALT, alanine transaminase; Cre, creatinine. Primary outcome No signs of LAST were observed from the administration of local anaesthetics to 24 hours postoperatively in all patients (Table 2 ) . Additionally, no abnormal EEG waves were observed during general anaesthesia. A representative EEG image during anaesthesia, characterized by alpha, theta, and delta waves, was presented in Supplementary Figure S3 . Table 2 Signs of LAST from the administration of local anaesthetics to postoperative 24 hours Symptoms of LAST Intraoperative n = 26 Postoperative n = 26 Abnormalities of EEG 0 - New-onset ECG irregularities 0 0 Dizziness - 0 Light-headedness - 0 Metallic taste - 0 Peri-oral numbness - 0 Tinnitus - 0 Seizure activity - 0 Loss of consciousness - 0 Death 0 0 LAST, local anaesthetic systemic toxicity; EEG, electroencephalography; ECG, electrocardiography. Secondary outcome Plasma concentrations of ropivacaine at all time points The time course of ropivacaine plasma concentrations was shown in Fig. 3 A and Fig. 3 B. Throughout the study, ropivacaine plasma concentrations were consistently below the established toxicity threshold of 2.2 µg mL − 1 in all patients. Peak plasma concentrations of ropivacaine occurred at 30 minutes (range, 20–60) after TAP block with a medium of 1.14 (range, 0.85–1.18), 1.42 (range, 1.29–1.80), and 1.96 (range, 1.47–2.06) µg mL − 1 for each dose group in the PP population, respectively (Fig. 3 and Supplementary Figure S4 ). The median plasma concentration of ropivacaine across all time points was 0.64 µg mL − in 1.5 mg kg − 1 group 1 , 0.99 µg mL − 1 in 2.0 mg kg − 1 group and 1.38 µg mL − 1 in 2.5 mg kg − 1 group in the PP analysis (Supplementary Figure S5 ). The ITT analysis found similar results: peak plasma concentrations of ropivacaine occurred at 37.5 minutes (range, 20–60) after TAP block with a medium of 1.05 (range,0.50–1.42), 1.36 (range, 0.72–1.89), and 1.45 (range, 1.19–2.06) µg mL − 1 for each dose group (Fig. 3 and Supplementary Figure S4 ). Plasma concentrations of lidocaine at all time points The plasma lidocaine concentrations in the PP and ITT population were shown in Fig. 3 C and 3 D. Consistent concentration timings were found in both the PP and ITT patient populations. Most patients exhibited a peak plasma concentration at 10 minutes after the initial bolus intravenous infusion, with median peak concentrations of 4.59 (range, 3.24–6.67) and 4.56 (range, 2.79–7.16) µg mL − 1 in the PP and ITT populations. The concentration dramatically dropped after 10 minutes post-bolus infusion and fluctuated between 1.68 and 4.22 µg mL − 1 for up to 2 hours, then gradually decreased in the PP populations (Supplementary Figure S6). Among these patients, three in the PP population and eight in the ITT population had plasma concentrations exceeding the established toxicity threshold of 5.0 µg mL − 1 at the 10 minutes timepoint (Fig. 3 and Supplementary Figure S7). Discussion This study explored the dose-risk relationship of LAST associated with the combined use of a 0.2% ropivacaine TAP block, administered at escalating doses of 1.5, 2.0, and 2.5 mg kg⁻¹, alongside a 2% intravenous lidocaine infusion (2 mg kg⁻¹ bolus, followed by continuous infusion at 2 mg kg⁻¹ h⁻¹) in adult patients undergoing colorectal cancer surgery. Although no clinical symptoms of LAST were observed and ropivacaine plasma concentrations remained well below the established toxicity threshold, 8 out of 26 patients had plasma lidocaine concentrations exceeding 5.0 µg mL⁻¹. These findings suggest that while the combination of 1.5–2.5 mg kg⁻¹ ropivacaine TAP block and intravenous lidocaine infusion may not result in overt clinical manifestations of LAST, potential risks may still need to be considered. Colorectal cancer surgery is one of the most frequently performed surgical procedures worldwide, with approximately 1.2 million patients undergoing this surgery annually. Inadequate postoperative pain management not only impedes recovery but also increases the risk of chronic pain development, which significantly impacts the patient’s long-term quality of life [ 26 ]. Ropivacaine is commonly used in TAP blocks for abdominal surgeries, due to its favorable pharmacological profile, including reduced motor blockade, lower cardiotoxicity, and extended analgesia duration[ 27 ]. Unlike previous reports of neurotoxic symptoms such as tongue paresthesia, metallic taste, and slurred speech in patients receiving 2.5 mg kg⁻¹ ropivacaine TAP blocks during cesarean sections [ 13 ], our study did not observe any signs of LAST. The discrepancy may be partly due to the ideal body weight other than actual body weight for dose calculations in our study, which helps mitigate the risk of overdose [ 10 , 13 ]. Additionally, we observed a dose-dependent increase in ropivacaine plasma concentration, with the 2.5 mg kg − 1 group exhibiting higher median levels compared to the two lower dose groups. A consistent time-concentration relationship was also noted, with peak plasma concentrations occurring between 20 and 60minutes post-TAP block, regardless of the total dose. This is consistent with the findings of Toju et al., who reported similar timing of peak concentrations following a 3 mg kg − 1 ropivacaine TAP block [ 28 ]. Given the stable pharmacokinetic profile of ropivacaine TAP blocks across dosages ranging from 1.5 to 3.0 mg kg − 1 , it appears that the peak plasma concentration period may require enhanced monitoring and management, particularly at higher doses, to minimize the potential for toxic effects. In this study, although some patients exhibited plasma lidocaine concentrations exceeding the commonly cited neurologic toxicity threshold of 5.0 µg mL − 1 [ 29 ], no LAST events were reported. This observation is consistent with findings by Suena et al., who reported no correlation between plasma lidocaine levels above 5.0 µg mL − 1 and LAST occurrence [ 30 ]. The variability in lidocaine toxicity thresholds, ranging from 5.0 to 15 µg mL − 1 [ 31 ], indicates a broader spectrum of safe plasma levels [ 14 , 29 , 32 ], possibly influenced by patient-specific factors such as gender, comorbidities, and physiological characteristics [ 33 , 34 ]. Notably, the toxicity thresholds established for single-drug use may not be appropriate when these drugs are combined. Although ropivacaine is primarily bound to albumin and lidocaine binds to α-1 acid glycoprotein (AGP), the two drugs may exhibit overlapping binding at the F1*S site of AGP[ 35 ]. This overlap could potentially elevate the free fraction of both drugs, thereby increasing the risk of LAST. Furthermore, the concurrent use of general anesthetics might alter the threshold for LAST threshold[ 36 ], adding further complexity to this clinical scenario. Nonetheless, our study represents a pioneering effort in evaluating the risk of concurrent administration of escalating doses of ropivacaine for TAP block and intravenous lidocaine infusion in patients undergoing colorectal surgery. This investigation highlights that careful attention to the potential risk of LAST is still warranted when using the two local anesthetics in combination. A key strength of our study was the implementation of EEG monitoring during general anaesthesia, which may help to detect potential neurotoxicity of local anaesthetics. Previous research has demonstrated that the plasma concentration threshold for lidocaine’s neurotoxicity (15 µg mL − 1 ) is lower than that for cardiovascular toxicity (21 µg mL − 1 ) [ 31 , 37 ]. Therefore, relying solely on ECG monitoring during general anaesthesia may underestimate its toxicity. Combining the EEG and ECG may offer a more comprehensive approach to detecting LAST under general anaesthesia. Moreover, the precise in local anaesthetic administration achieved through ultrasound guidance by experienced anaesthesiologists further minimized the risk of inadvertent leakage into the surrounding musculature, which can affect drug absorption and increase the risk of toxicity [ 38 ]. Rosenberg et al. have recommended tailoring local anaesthetic dosage based on technique specificity rather than a maximum safe dose [ 39 ]. Our study also acknowledged several limitations. Firstly, the small sample size, while a limitation, was a necessary consequence of adhering to the 3 + 3 dose-escalation trial design. Given the undefined toxicity risks associated with the combined use of the two local anesthetics, a minimal-risk exposure strategy was adopted to prioritize patient safety. As a result, the sample size was limited, preventing the ability to draw definitive conclusions about safety. Secondly, we cannot assess the analgesic efficacy due to the small sample size. While the dose levels for ropivacaine and lidocaine were selected based on existing studies reporting their effectiveness for postoperative pain relief in various surgical settings, either alone or in combination [ 8 , 12 , 13 ], it remains uncertain whether higher doses of ropivacaine would offer superior analgesia. Thirdly, we did not measure the unbound (free) concentration of ropivacaine or lidocaine. The toxicity of local anesthetics, however, is primarily determined by the free fraction of the drug, which represents the pharmacologically active component, rather than the total plasma concentration, this limits our ability to assess toxicity accurately. Finally, the toxicity levels referenced for intravenous lidocaine and ropivacaine TAP block were based on the established safety thresholds for each drug when used individually; however, these thresholds may not be suitable when the drugs are combined. The lack of a universally accepted toxicity threshold for their combined use presents a significant challenge in evaluating their safety. Future studies are needed to define safe thresholds and establish more precise guidelines for their combined use. Conclusions Although no signs of LAST were observed with the combination of a 1.5 to 2.5 mg kg − 1 ropivacaine TAP block and a fixed-rate intravenous lidocaine infusion, caution is strongly advised regarding the risk of LAST when using this combination. Safe thresholds for the combined use of these local anesthetics have not yet been established, underscoring the need for further studies to define these limits more accurately. Abbreviations TAP: Transversus abdominis plane; LAST: Local anesthetic systemic toxicity; MTD: Maximum tolerated dose; ASA: Society of Anaesthesiologists; ECG: Electrocardiography; EEG: Electroencephalography; PSI: Patient State Index; PACU: Post-anaesthesia care unit; IBW: Ideal body weight; SD: Standard deviation; IQR: Interquartile range; PP: Per-protocol; ITT: Intention-to-treat; CONSORT: Consolidated Standards of Reporting Trials Declarations Acknowledgements Not applicable. Authors’ contributions Li Zhou, Lulong Bo and Chunling Jiang: these authors helped to design the study and revise the manuscript; Mengmeng Zhou, Yan Xu: these authors helped to analyse and intepretate data; Xiaoting Hao: this author helped to analyse electroencephalogram. Feng Yu, Jingwen Wu, Lajing Luowu, Qianqian Tang, Kun Shao, Mao Ye: these authors helped to collect date; All authors helped to draft the manuscript. Funding: This work was supported by Sichuan Science and Technology Program [grant number 2023ZYD0168], Wu JiePing Medical Foundation [grant number 320.6750.2022-05-3]. Data availability The datasets generated and analysed during the current study are available from the corresponding author on reasonable request. Ethics approval and consent to participate This study was conducted in accordance with the Declaration of Helsinki. Ethical approval was obtained from the Ethics Committee of West China Hospital, Sichuan University (approval number HX20201180-1). All patients provided informed consent and was enrolled after registration. Consent for publication Not applicable. Competing interests The authors declare no competing interests. Author details 1 Department of Anaesthesiology, West China Hospital, Sichuan University & The Research Units of West China (2018RU012), Chinese Academy of Medical Sciences, Chengdu, China. 2 Department of Neurology, West China Hospital, Sichuan University, Chengdu, China. 3 Department of Anaesthesiology, Xinxiang Central Hospital, Xinxiang, China. 4 Faculty of Anaesthesiology, Changhai Hospital, Naval Medical University, Shanghai, China. References Gan TJ. Poorly controlled postoperative pain: prevalence, consequences, and prevention. J Pain Res 2017; 10: 2287-2298. Hyland SJ, Wetshtein AM, Grable SJ, Jackson MP. Acute Pain Management Pearls: A Focused Review for the Hospital Clinician. Healthcare (Basel) 2022; 11. Zhu QQ, Qu L, Su T et al. Risk Factors of Acute Pain in Elderly Patients After Laparoscopic Radical Resection of Colorectal Cancer. Surg Laparosc Endosc Percutan Tech 2024; 34: 43-47. Irani JL, Hedrick TL, Miller TE et al. Clinical practice guidelines for enhanced recovery after colon and rectal surgery from the American Society of Colon and Rectal Surgeons and the Society of American Gastrointestinal and Endoscopic Surgeons. Surg Endosc 2023; 37: 5-30. Liu T, Yang J, Wang Y et al. Interfascial plane block: a new anesthetic technique. Anesthesiol Periop Sci 2023; 1: 31. Tran DQ, Bravo D, Leurcharusmee P, Neal JM. Transversus Abdominis Plane Block: A Narrative Review. Anesthesiology 2019; 131: 1166-1190. Peltrini R, Cantoni V, Green R et al. Efficacy of transversus abdominis plane (TAP) block in colorectal surgery: a systematic review and meta-analysis. Tech Coloproctol 2020; 24: 787-802. Xu Y, Ye M, Liu F et al. Efficacy of prolonged intravenous lidocaine infusion for postoperative movement-evoked pain following hepatectomy: a double-blinded, randomised, placebo-controlled trial. Br J Anaesth 2023; 131: 113-121. Yang W, Yan S, Yu F, Jiang C. Appropriate Duration of Perioperative Intravenous Administration of Lidocaine to Provide Satisfactory Analgesia for Adult Patients Undergoing Colorectal Surgery: A Meta-Analysis of Randomized Controlled Trials. Anesth Analg 2023; 136: 494-506. Foo I, Macfarlane AJR, Srivastava D et al. The use of intravenous lidocaine for postoperative pain and recovery: international consensus statement on efficacy and safety. Anaesthesia 2021; 76: 238-250. Bailey MA, Toner AJ, Corcoran TB. A survey of perioperative intravenous lidocaine use by anaesthetists in Australia and New Zealand. Anaesth Intensive Care 2020; 48: 53-58. McDonnell JG, Curley G, Carney J et al. The analgesic efficacy of transversus abdominis plane block after cesarean delivery: a randomized controlled trial. Anesth Analg 2008; 106: 186-191. Griffiths JD, Le NV, Grant S et al. Symptomatic local anaesthetic toxicity and plasma ropivacaine concentrations after transversus abdominis plane block for Caesarean section. Br J Anaesth 2013; 110: 996-1000. Beaussier M, Delbos A, Maurice-Szamburski A et al. Perioperative Use of Intravenous Lidocaine. Drugs 2018; 78: 1229-1246. Yang S, Wang SJ, Ji Y. An integrated dose-finding tool for phase I trials in oncology. Contemp Clin Trials 2015; 45: 426-434. Eagleman SL, Drover CM, Li X et al. Offline comparison of processed electroencephalogram monitors for anaesthetic-induced electroencephalogram changes in older adults. Br J Anaesth 2021; 126: 975-984. Yurttas T, Djurdjevic M, Schnider TW, Filipovic M. Analgesic efficacy of systemic lidocaine using lean body mass based dosing regime versus placebo in bariatric surgery: a prospective, randomised, double-blind, placebo-controlled, single-centre study. Br J Anaesth 2023; 131: 122-129. Griffiths JD, Barron FA, Grant S et al. Plasma ropivacaine concentrations after ultrasound-guided transversus abdominis plane block. Br J Anaesth 2010; 105: 853-856. El-Boghdadly K, Pawa A, Chin KJ. Local anesthetic systemic toxicity: current perspectives. Local Reg Anesth 2018; 11: 35-44. Kaplan PW. The EEG of status epilepticus. J Clin Neurophysiol 2006; 23: 221-229. Spitzer D, Wenger KJ, Neef V et al. Local Anesthetic-Induced Central Nervous System Toxicity during Interscalene Brachial Plexus Block: A Case Series Study of Three Patients. J Clin Med 2021; 10. Noachtar S, Rémi J. The role of EEG in epilepsy: a critical review. Epilepsy Behav 2009; 15: 22-33. Qin WW, Jiao Z, Zhong MK et al. Simultaneous determination of procaine, lidocaine, ropivacaine, tetracaine and bupivacaine in human plasma by high-performance liquid chromatography. J Chromatogr B Analyt Technol Biomed Life Sci 2010; 878: 1185-1189. Scott DB, Lee A, Fagan D et al. Acute toxicity of ropivacaine compared with that of bupivacaine. Anesth Analg 1989; 69: 563-569. Kurzrock R, Lin CC, Wu TC et al. Moving Beyond 3+3: The Future of Clinical Trial Design. Am Soc Clin Oncol Educ Book 2021; 41: e133-e144. Lindberg M, Franklin O, Svensson J, Franklin KA. Postoperative pain after colorectal surgery. Int J Colorectal Dis 2020; 35: 1265-1272. Ping C, Lin QS, Lin XZ. Optimal concentration of the transversus abdominis plane block in enhanced recovery after surgery protocols for patients of advanced age undergoing laparoscopic rectal cancer surgery. J Int Med Res 2018; 46: 4437-4446. Toju K, Shiraishi K, Hakozaki T et al. Plasma ropivacaine concentration following ultrasound-guided subcostal transversus abdominis plane block in adults. J Anesth 2015; 29: 146-148. Foldes FF, Molloy R, Mc NP, Koukal LR. Comparison of toxicity of intravenously given local anesthetic agents in man. J Am Med Assoc 1960; 172: 1493-1498. Sucena M, Cachapuz I, Lombardia E et al. Plasma concentration of lidocaine during bronchoscopy. Rev Port Pneumol 2004; 10: 287-296. DeToledo JC. Lidocaine and seizures. Ther Drug Monit 2000; 22: 320-322. Bromage PR, Robson JG. Concentrations of lignocaine in the blood after intravenous, intramuscular epidural and endotracheal administration. Anaesthesia 1961; 16: 461-478. Macfarlane AJR, Gitman M, Bornstein KJ et al. Updates in our understanding of local anaesthetic systemic toxicity: a narrative review. Anaesthesia 2021; 76 Suppl 1: 27-39. Miller RJ, Cameron AJ, Dimech J et al. Plasma Ropivacaine Concentrations Following Local Infiltration Analgesia in Total Knee Arthroplasty: A Pharmacokinetic Study to Determine Safety Following Fixed-Dose Administration. Reg Anesth Pain Med 2018; 43: 347-351. Taheri S, Cogswell LP, 3rd, Gent A, Strichartz GR. Hydrophobic and ionic factors in the binding of local anesthetics to the major variant of human alpha1-acid glycoprotein. J Pharmacol Exp Ther 2003; 304: 71-80. Dougherty PM, Raja SN. Chapter 2 - Neurochemist ry of Somatosensory and Pain Processing. In Benzon HT, Raja SN, Molloy RE et al. (eds): Essentials of Pain Medicine and Regional Anesthesia (Second Edition). Philadelphia: Churchill Livingstone 2005; 7-14. Weinberg L, Peake B, Tan C, Nikfarjam MJWJoA. Pharmacokinetics and pharmacodynamics of lignocaine: A review. 2015; 4: 17-29. Kato N, Fujiwara Y, Harato M et al. Serum concentration of lidocaine after transversus abdominis plane block. J Anesth 2009; 23: 298-300. Rosenberg PH, Veering BT, Urmey WF. Maximum recommended doses of local anesthetics: a multifactorial concept. Reg Anesth Pain Med 2004; 29: 564-575; discussion 524. Additional Declarations No competing interests reported. Supplementary Files supplementaryfile.docx Appendix A. Supplementary data Supplementary Figure S1: Image of the transversus abdominis plane block. EO, external oblique; IO, internal oblique; TA, transversus abdominis; Grey curve: local anesthetic distribution Supplementary Figure S2: Patients enrolment timeline. Supplementary Figure S3: A representative image of electroencephalography during general anaesthesia Supplementary Figure S4: Median plasma concentration of ropivacaine at each time point in the PP analysis(A) and ITT analysis(B). PP, per-protocol; ITT, intention-to-treat. Supplementary Figure S5: Median plasma concentration of ropivacaine within each group in the PP analysis(A) and ITT analysis(B). PP, per-protocol; ITT, intention-to-treat. Supplementary Figure S6: Median plasma concentration of lidocaine at each time point in the PP analysis(A) and ITT analysis(B). PP, per-protocol; ITT, intention-to-treat. Supplementary Figure S7: Median plasma concentration of lidocaine in the PP analysis and ITT analysis. PP, per-protocol; ITT, intention-to-treat. Cite Share Download PDF Status: Published Journal Publication published 22 Jul, 2025 Read the published version in BMC Anesthesiology → Version 1 posted Editorial decision: Revision requested 09 Jun, 2025 Editor assigned by journal 05 Jun, 2025 Reviewers invited by journal 25 Mar, 2025 Submission checks completed at journal 25 Mar, 2025 First submitted to journal 22 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5690114","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":433834355,"identity":"811099ff-75a2-424a-921d-4acb98a9e798","order_by":0,"name":"Mengmeng Zhou","email":"","orcid":"","institution":"West China Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Mengmeng","middleName":"","lastName":"Zhou","suffix":""},{"id":433834356,"identity":"d418c63a-080e-4db2-b6b4-48013c47832b","order_by":1,"name":"Feng Yu","email":"","orcid":"","institution":"West China Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Feng","middleName":"","lastName":"Yu","suffix":""},{"id":433834357,"identity":"d8d2cada-103b-476d-8bf5-1576b360caca","order_by":2,"name":"Yan Xu","email":"","orcid":"","institution":"West China Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Yan","middleName":"","lastName":"Xu","suffix":""},{"id":433834358,"identity":"8c077493-6445-46b7-ba27-46562b48ac40","order_by":3,"name":"Jingwen Wu","email":"","orcid":"","institution":"West China Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Jingwen","middleName":"","lastName":"Wu","suffix":""},{"id":433834359,"identity":"56589d15-aabe-4a35-923b-f3d354abe0be","order_by":4,"name":"Lajing Luowu","email":"","orcid":"","institution":"West China Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Lajing","middleName":"","lastName":"Luowu","suffix":""},{"id":433834360,"identity":"c83f6138-54a9-4e98-a69b-1534c32e6d10","order_by":5,"name":"Qianqian Tang","email":"","orcid":"","institution":"West China Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Qianqian","middleName":"","lastName":"Tang","suffix":""},{"id":433834361,"identity":"0f559e4c-8f1c-447d-b0d3-efffe566ab26","order_by":6,"name":"Xiaoting Hao","email":"","orcid":"","institution":"West China Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Xiaoting","middleName":"","lastName":"Hao","suffix":""},{"id":433834362,"identity":"04a4e3ae-0fc8-4bea-90da-6431f81c3faa","order_by":7,"name":"Kun Shao","email":"","orcid":"","institution":"Xinxiang Central 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14:23:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5690114/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5690114/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12871-025-03225-5","type":"published","date":"2025-07-22T15:57:37+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":79318817,"identity":"323b821d-f987-444a-bcf2-f1cc4627a646","added_by":"auto","created_at":"2025-03-27 04:12:23","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":63329,"visible":true,"origin":"","legend":"\u003cp\u003eSchema of the 3+3 design. DLT: dose-limiting toxicity.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5690114/v1/0e19fd795946fd09900f85d3.jpg"},{"id":79319833,"identity":"a9c5976f-b2c6-4447-a1c7-c73c9ccb7577","added_by":"auto","created_at":"2025-03-27 04:20:23","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":82140,"visible":true,"origin":"","legend":"\u003cp\u003eConsolidated Standards of Reporting Trials (CONSORT) flow diagram.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5690114/v1/c8ffc7542246e5d40687dbd2.jpg"},{"id":79319834,"identity":"2d7e9c14-69d3-4117-9d30-a31008ff64b7","added_by":"auto","created_at":"2025-03-27 04:20:24","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":107368,"visible":true,"origin":"","legend":"\u003cp\u003ePlasma concentrations of ropivacaine and lidocaine at each time point in the PP analysis and ITT analysis. A, plasma concentrations of ropivacaine at each time point in the PP analysis (n=9); B, plasma concentrations of ropivacaine at each time point in the ITT analysis (n=26); C, plasma concentrations of lidocaine at each time point in the PP analysis (n=9); D, plasma concentrations of lidocaine at each time point in the ITT analysis (n=26). PP, per-protocol; ITT, intention-to-treat.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5690114/v1/902899570493662484180efd.jpg"},{"id":87756840,"identity":"17f5f575-373f-4647-9cc4-7995b314cb73","added_by":"auto","created_at":"2025-07-28 16:09:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1240113,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5690114/v1/f3034b62-ac7b-4bb9-b41f-0e1f4ff7ee0b.pdf"},{"id":79321882,"identity":"bb1a5398-ba3d-465a-9942-e934a6386765","added_by":"auto","created_at":"2025-03-27 04:36:24","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":4664117,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAppendix A. Supplementary data\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSupplementary \u003cstrong\u003eFigure S1\u003c/strong\u003e: Image of the transversus abdominis plane block.\u003cstrong\u003e \u003c/strong\u003eEO, external oblique; IO, internal oblique; TA, transversus abdominis; Grey curve: local anesthetic distribution\u003c/p\u003e\n\u003cp\u003eSupplementary \u003cstrong\u003eFigure S2\u003c/strong\u003e: Patients enrolment timeline.\u003c/p\u003e\n\u003cp\u003eSupplementary \u003cstrong\u003eFigure S3\u003c/strong\u003e: A representative image of electroencephalography during general anaesthesia\u003c/p\u003e\n\u003cp\u003eSupplementary \u003cstrong\u003eFigure S4: \u003c/strong\u003eMedian plasma concentration of ropivacaine at each time point in the PP analysis(A) and ITT analysis(B). PP, per-protocol; ITT, intention-to-treat.\u003c/p\u003e\n\u003cp\u003eSupplementary \u003cstrong\u003eFigure S5\u003c/strong\u003e: Median plasma concentration of ropivacaine within each group in the PP analysis(A) and ITT analysis(B). PP, per-protocol; ITT, intention-to-treat.\u003c/p\u003e\n\u003cp\u003eSupplementary \u003cstrong\u003eFigure S6\u003c/strong\u003e: Median plasma concentration of lidocaine at each time point in the PP analysis(A) and ITT analysis(B). PP, per-protocol; ITT, intention-to-treat.\u003c/p\u003e\n\u003cp\u003eSupplementary \u003cstrong\u003eFigure S7\u003c/strong\u003e: Median plasma concentration of lidocaine in the PP analysis and ITT analysis. PP, per-protocol; ITT, intention-to-treat.\u003c/p\u003e","description":"","filename":"supplementaryfile.docx","url":"https://assets-eu.researchsquare.com/files/rs-5690114/v1/f3493093cbd53b2f64d6c5eb.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Combining ropivacaine transversus abdominis plane block with intravenous lidocaine infusion in adults undergoing colorectal cancer surgery: an open-label, dose-escalation exploratory trial","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePostoperative pain severely impairs early mobility and increases the risk of postoperative complications, causing prolonged hospital stays and delayed recovery [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Despite advancements in pain management, achieving optimal postoperative analgesia remains a challenge [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In colorectal cancer surgery, postoperative pain, especially movement-evoked pain, affects over 50% of patients, highlighting the urgent need for effective pain management strategies [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMultimodal analgesia protocols have become increasingly prevalent in clinical practice to address these challenges [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Among these approaches, the transversus abdominis plane (TAP) block, which provides extensive pain relief by targeting a broad range of sensory nerves [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], and intravenous lidocaine, commonly used perioperatively for its anti-hyperalgesic and anti-inflammatory properties, have both demonstrated significant efficacy in pain relief and opioids reduction [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], particularly in colorectal surgery [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Our previous study indicated that combining intravenous lidocaine with local wound infiltration using ropivacaine provided superior pain relief compared to ropivacaine infiltration alone [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. However, this combination also raises significant safety concerns, particularly regarding the risk of local anesthetic systemic toxicity (LAST) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDespite these safety concerns, a survey of anesthetists in Australian and New Zealand revealed that over 25% of respondents utilized both analgesia protocols in surgical patients [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Although international consensus guideline recommends a 4-hour interval between the administration of these local anesthetics to minimize this risk [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], adherence to these guidelines in clinical practice remains suboptimal. Reports indicated that only 37% of anaesthesiologists discontinued lidocaine infusion before performing a local block, while 44% merely reduced the local anesthetic dose instead [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. This discrepancy between recommended guidelines and actual clinical practice highlights a significant gap, underscoring the need for further investigation into the potential LAST risk when the two local anesthetics are combined and administered across multiple routes.\u003c/p\u003e \u003cp\u003eGiven that the effective dosage range for ropivacaine in TAP blocks is reported to be 1.5 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e to 2.5 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], and intravenous lidocaine is typically administered as a bolus dose of 1.5-2 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e followed by a continuous infusion at 1.5-2 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003eh\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], our study will fix the lidocaine infusion dose and initiate ropivacaine at lower doses for TAP blocks using a dose-escalation strategy to assess the dose-risk relationship.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eEthics statements\u003c/h2\u003e \u003cp\u003eThis trial was registered prospectively with ClinicalTrials.gov (NCT06006026, principal investigator: Chunling Jiang, date of registration: August 23, 2023). Ethical approval was obtained from the Ethics Committee of West China Hospital, Sichuan University (approval number HX20201180-1). All patients provided informed consent and were enrolled after registration.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy design\u003c/h3\u003e\n\u003cp\u003eThis open-label, dose-escalation trial followed a 3\u0026thinsp;+\u0026thinsp;3 model to assess whether escalating doses of ropivacaine, as observed in previous studies [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], when combined with a fixed intravenous dose of lidocaine [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], increased the risk of LAST. The trial was conducted at the West China Hospital of Sichuan University from August 28, 2023, to May 15, 2024.\u003c/p\u003e \u003cp\u003eThe 3\u0026thinsp;+\u0026thinsp;3 dose-escalation model, commonly employed in Phase I trials, was selected in this study due to the uncertainty surrounding the toxicity of combining the two local anesthetics. This approach minimized risk by limiting exposure. The sample size was determined by the number of dose levels tested, with additional patients being included only if necessary to replace incomplete data sets or to further assess potential adverse events.\u003c/p\u003e\n\u003ch3\u003ePatient recruitment\u003c/h3\u003e\n\u003cp\u003eWe included patients aged 18\u0026ndash;65 years with an American Society of Anaesthesiologists (ASA) physical status of I\u0026ndash;II, who were scheduled for elective colorectal surgery. The exclusion criteria were body weight\u0026thinsp;\u0026lt;\u0026thinsp;40 kg or \u0026gt;\u0026thinsp;100 kg, cardiac rhythm disorders or systolic heart failure (including second- and third-degree heart block and ejection fraction\u0026thinsp;\u0026lt;\u0026thinsp;50%), severe liver dysfunction (alanine aminotransferase, aspartate aminotransferase, or bilirubin levels 2.5 times higher than normal), severe renal dysfunction (creatinine clearance rate\u0026thinsp;\u0026lt;\u0026thinsp;60 mL/min), contraindications to lidocaine or ropivacaine, and communication difficulties.\u003c/p\u003e\n\u003ch3\u003eAnaesthesia management\u003c/h3\u003e\n\u003cp\u003eUpon arrival at the operating room, patients were monitored with electrocardiography (ECG), blood oxygen saturation, blood pressure monitoring, and electroencephalography (EEG). General anaesthesia was induced with midazolam (2 mg), propofol (1.5\u0026ndash;2.5 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e), sufentanil (0.2\u0026ndash;0.3 \u0026micro;g kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e), and cisatracurium (0.2 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e). After tracheal intubation, anaesthesia was maintained with remifentanil (0.1\u0026ndash;0.2 \u0026micro;g kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) and desflurane or sevoflurane in a mixture of 40% air and 60% oxygen to maintain the Patient State Index (PSI) within a range of 25\u0026ndash;50, as monitored by the Masimo Root monitor [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. After surgery, all patients were extubated in the operating room and transferred to the post-anaesthesia care unit (PACU), where they were monitored according to the institutional PACU protocol [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eStudy intervention\u003c/h3\u003e\n\u003cp\u003eAfter anaesthesia induction, an experienced anaesthesiologist performed bilateral TAP blocks using high-frequency linear array ultrasound probes (AnaesusME7 Mindray Bio; Medical Electronics, Shenzhen, China). Success of the TAP block was confirmed using the technique described by Griffiths and colleagues[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] (Supplementary \u003cb\u003eFigure S1\u003c/b\u003e). TAP blocks were administered using a dose-escalation approach based on ideal body weight (IBW, IBW\u0026thinsp;=\u0026thinsp;45.4\u0026thinsp;+\u0026thinsp;0.89ⅹ(height\u0026ndash;152.4) (+\u0026thinsp;4.5 if male)[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], initiating with the lowest dose for three initial patients. Concurrently, patients received an intravenous infusion of lidocaine at a dose of 2.0 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e over a duration of 10 minutes, followed by a continuous infusion at 2.0 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e h\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e until the end of surgery. Doses were also calculated based on IBW. If no signs of LAST were observed, an additional three patients were recruited at the next higher dose. Notably, if blood samples could not be obtained for measurement of the plasma concentrations, new patients were enrolled until at least three patients per dosage group had complete blood sample data. In the event of an adverse event related to LAST, three additional patients were enrolled at the same dose level (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The initial dose selection was based on previous studies confirming its safety and efficacy [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The dose at which no more than one of the three patients experienced an adverse event related to LAST was designated as the recommended phase 2 dose. Three dose levels were evaluated: 1.5 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, 2.0 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, and 2.5 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e of 0.2% ropivacaine. Further dose escalation beyond 2.5 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e was not pursued due to potential neurotoxicity reported with 3.0 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eAdverse event management\u003c/h2\u003e \u003cp\u003eIn the event that patients experienced severe signs of LAST, characterised by generalised seizures, life-threatening arrhythmia or unexplained loss of consciousness, local anaesthetics were discontinued immediately and a 20% lipid emulsion was administered [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Adverse events and their treatments were meticulously documented.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy outcomes\u003c/h3\u003e\n\u003cp\u003eThe primary outcome was the occurrence of LAST, identified by clinical symptoms such as dizziness, light-headedness, metallic taste, perioral numbness, tinnitus, seizures, unexplained loss of consciousness, or new-onset ECG irregularities [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], occurring from the administration of local anesthetics up to 24 hours postoperatively. Intraoperative EEG abnormalities, such as continuous or recurrent focal or generalized spikes, sharp waves, or rhythmic theta or delta activity, were also considered as indicators of LAST [\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSecondary outcomes included plasma concentrations of ropivacaine and lidocaine at various time points (10, 20, 30, 45, 60, and 90 minutes and 2, 4, 6, 12, and 24 hours) following the completion of bilateral TAP blocks and the initiation of intravenous lidocaine infusion.\u003c/p\u003e\n\u003ch3\u003eData collection\u003c/h3\u003e\n\u003cp\u003eBlood samples were obtained from the contralateral side of the lidocaine infusion site. Samples were processed for serum storage and batch analysis using high-performance liquid chromatography with carbamazepine as the internal standard [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIntraoperative adverse events, including new-onset ECG irregularities or EEG abnormalities, such as continuous or recurrent focal or generalized spikes, sharp waves, or rhythmic theta or delta activity [\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], were assessed by an experienced anaesthesiologist trained in ECG and EEG. After extubation, adverse events, including signs, or ECG changes related to LAST [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], were assessed and monitored by trained assessors at the bedside for up to 24 hours postoperatively. All EEG recordings were ultimately evaluated by a neurologist to confirm again. Additionally, postoperative analgesic consumption during 24 hours was recorded and converted into intravenous morphine equivalents (mg) using the Practical Pain Management calculator (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://opioidcalculator.practicalpainmanagement.com/\u003c/span\u003e\u003cspan address=\"https://opioidcalculator.practicalpainmanagement.com/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), with the NRS score also documented at 24 hours postoperatively.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003eSample size estimation\u003c/h2\u003e \u003cp\u003eThis study followed a 3\u0026thinsp;+\u0026thinsp;3 design, with the final sample size depending on real-time response of the patients at each dose level. The maximum sample size was typically six times the number of dose levels, with complete blood samples at each time point [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eGeneral statistical analysis\u003c/h2\u003e \u003cp\u003eResults of descriptive analysis of normally distributed variables were presented as mean and standard deviation (SD), whereas non-normally distributed data were presented as median (interquartile range, IQR) or median (range). Categorical variables were presented as the number of cases (percentage). Primary analyses were based on the per-protocol (PP) population, and secondary sensitivity analyses were done on the intention-to-treat (ITT) population for the primary and secondary outcomes. The normality of data distribution was assessed by evaluating histograms and using the Shapiro\u0026ndash;Wilk test to determine the appropriate comparison tests (parametric versus nonparametric). Statistical analysis was performed using SPSS software (version 22.0; IBM Corp.).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eDuring the study, 45 patients were screened for eligibility. Of these, 26 were involved and treated with a combination of a ropivacaine TAP block and lidocaine intravenous infusion according to their assigned dose (Supplementary \u003cb\u003eFigure S2\u003c/b\u003e). Blood samples were missed at certain time points for 17 patients. Consequently, the PP analysis included 9 patients. The patient enrollment process is illustrated in the Consolidated Standards of Reporting Trials (CONSORT) flow diagram shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003ePP, per-protocol; ITT, intention-to-treat.\u003c/p\u003e \u003cp\u003eThe characteristics of the enrolled patients are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The median age of the patients was 57 years (IQR: 48\u0026ndash;61), with 13 (50%) being male and body mass index (BMI) 23.6 kg m\u003csup\u003e\u0026minus;\u0026thinsp;2\u003c/sup\u003e (IQR: 22.5\u0026ndash;25.8). The duration of anaesthesia was 3.9 hours (IQR: 3.3\u0026ndash;4.3). The median doses of lidocaine and ropivacaine administered during anaesthesia were 456 mg (IQR: 403\u0026ndash;528) and 100 mg (IQR: 85\u0026ndash;136), respectively. Intraoperative hemodynamic changes over times were presented in Supplementary Table\u0026nbsp;1. Postoperative morphine equivalent consumption during 24 hours and the NRS score at 24 hours were also provided in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristic and perioperative data of all patients.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.5 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e group\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;10\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.0mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e group\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;8\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.5mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e group\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;8\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAll\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;26\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBaseline characteristic\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eAge (y)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58(52\u0026ndash;64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e58(47\u0026ndash;64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e50(47\u0026ndash;58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e57(48\u0026ndash;61)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eSex (male, n [%])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5(50.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3(37.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5(62.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13(50.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eHeight (cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e161(152\u0026ndash;168)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e159(155\u0026ndash;167)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e167(160\u0026ndash;170)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e162(157\u0026ndash;168)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eWeight (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58(53\u0026ndash;67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60(54\u0026ndash;73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e69(62\u0026ndash;73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e61(55\u0026ndash;71)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eBMI (kg m\u003csup\u003e\u0026minus;\u0026thinsp;2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22.8(22.3\u0026ndash;24.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24.2(22.1\u0026ndash;25.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e24.5(22.9\u0026ndash;27.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e23.6(22.5\u0026ndash;25.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eBaseline BP (mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eSBP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e123(119\u0026ndash;142)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e121(112\u0026ndash;138)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e122(114\u0026ndash;140)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e122(118\u0026ndash;140)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eDBP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e76(67\u0026ndash;88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e73(66\u0026ndash;81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e76(66\u0026ndash;83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e75(67\u0026ndash;84)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eHR (beats/min)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e73(61\u0026ndash;79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e66(56\u0026ndash;87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e70(63\u0026ndash;75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e71(62\u0026ndash;77)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eASA physical status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (n, [%])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9(90.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7(87.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8(100.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e24(92.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (n, [%])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(10.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1(12.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0(0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2(7.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePreoperative chemotherapy (n, [%])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4(40.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1(12.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1(12.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6(23.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePreoperative test\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHb (g L\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e128(117\u0026ndash;132)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e117(102\u0026ndash;132)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e110(102\u0026ndash;119)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e118(105\u0026ndash;131)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eALT (IU L\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19(11\u0026ndash;34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16(9\u0026ndash;23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12(8\u0026ndash;31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e16(10\u0026ndash;29)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAST (IU L\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23(14\u0026ndash;34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20(15\u0026ndash;21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e17(15\u0026ndash;29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e19(14\u0026ndash;31)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAlb (g L\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40(37\u0026ndash;42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40(38\u0026ndash;42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e42(42\u0026ndash;43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e41(38\u0026ndash;42)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCre (mmol L\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e70(57\u0026ndash;75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e62(56\u0026ndash;69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e84(62\u0026ndash;90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e68(58\u0026ndash;84)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIntraoperative data\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eRopivacaine dose (mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e83(67\u0026ndash;93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e102(95\u0026ndash;126)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e157(131\u0026ndash;164)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e100(85\u0026ndash;136)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eLidocaine bolus\u003c/p\u003e \u003cp\u003edose (mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e111(89\u0026ndash;124)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e102(95\u0026ndash;126)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e126(105\u0026ndash;131)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e111(98\u0026ndash;128)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eLidocaine total\u003c/p\u003e \u003cp\u003edose (mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e446(367\u0026ndash;483)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e487(426\u0026ndash;623)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e477(378\u0026ndash;551)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e456(403\u0026ndash;528)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eRemifentanil dose (mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.5(1.1\u0026ndash;1.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.6(1.0-1.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.2(0.9\u0026ndash;1.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.4(1.0-1.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eSufentanil dose (\u0026micro;g)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27.5(20-32.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27.5(25\u0026ndash;30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e27.5(23.1\u0026ndash;34.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e27.5(24.4\u0026ndash;32.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eAnaesthesia\u003c/p\u003e \u003cp\u003eduration (h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.9(3.1\u0026ndash;4.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.4(4.0-4.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.3(3.2\u0026ndash;3.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.9(3.3\u0026ndash;4.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eSurgery duration (h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.6(2.0\u0026ndash;3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.8(2.5\u0026ndash;3.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.3(2.1\u0026ndash;2.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.6(2.2-3.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eFluid infusion (ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1450(1200\u0026ndash;1625)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1850(1450\u0026ndash;2300)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1300(1225\u0026ndash;1888)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1525(1300\u0026ndash;1700)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eBlood loss (ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20(20\u0026ndash;30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20(20\u0026ndash;28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25(20\u0026ndash;48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e20(20\u0026ndash;30)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eUrine output (ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e200(138\u0026ndash;325)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e375(263\u0026ndash;675)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e175(113\u0026ndash;300)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e275(150\u0026ndash;400)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePostoperative 24 hours\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eMorphine equivalent (mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36.8\u0026thinsp;\u0026plusmn;\u0026thinsp;12.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e37.8\u0026thinsp;\u0026plusmn;\u0026thinsp;11.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e35.5\u0026thinsp;\u0026plusmn;\u0026thinsp;11.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e36.7\u0026thinsp;\u0026plusmn;\u0026thinsp;11.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eNRS score at rest\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.4 (0.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.5 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.4 (0.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.4(0.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eNRS score during movement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.6 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.6 (0.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.2 (0.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.5(0.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eData are presented as absolute number (%), median (interquartile range); M, male; F, female; BMI, body mass index; BP, blood pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; Hb, haemoglobin; AST, aspartate aminotransferase; ALT, alanine transaminase; Cre, creatinine.\u003c/p\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003ePrimary outcome\u003c/h2\u003e \u003cp\u003eNo signs of LAST were observed from the administration of local anaesthetics to 24 hours postoperatively in all patients (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. Additionally, no abnormal EEG waves were observed during general anaesthesia. A representative EEG image during anaesthesia, characterized by alpha, theta, and delta waves, was presented in Supplementary Figure \u003cb\u003eS3\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSigns of LAST from the administration of local anaesthetics to postoperative 24 hours\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSymptoms of LAST\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIntraoperative\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;26\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePostoperative\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;26\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbnormalities of EEG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNew-onset ECG irregularities\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDizziness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLight-headedness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetallic taste\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeri-oral numbness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTinnitus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSeizure activity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLoss of consciousness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeath\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eLAST, local anaesthetic systemic toxicity; EEG, electroencephalography; ECG, electrocardiography.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eSecondary outcome\u003c/h2\u003e \u003cdiv id=\"Sec17\" class=\"Section3\"\u003e \u003ch2\u003ePlasma concentrations of ropivacaine at all time points\u003c/h2\u003e \u003cp\u003eThe time course of ropivacaine plasma concentrations was shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA and Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB. Throughout the study, ropivacaine plasma concentrations were consistently below the established toxicity threshold of 2.2 \u0026micro;g mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e in all patients. Peak plasma concentrations of ropivacaine occurred at 30 minutes (range, 20\u0026ndash;60) after TAP block with a medium of 1.14 (range, 0.85\u0026ndash;1.18), 1.42 (range, 1.29\u0026ndash;1.80), and 1.96 (range, 1.47\u0026ndash;2.06) \u0026micro;g mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e for each dose group in the PP population, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Supplementary Figure \u003cb\u003eS4\u003c/b\u003e). The median plasma concentration of ropivacaine across all time points was 0.64 \u0026micro;g mL\u003csup\u003e\u0026minus;\u003c/sup\u003e in 1.5 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e group \u003csup\u003e1\u003c/sup\u003e, 0.99 \u0026micro;g mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e in 2.0 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e group and 1.38 \u0026micro;g mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e in 2.5 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e group in the PP analysis (Supplementary Figure \u003cb\u003eS5\u003c/b\u003e). The ITT analysis found similar results: peak plasma concentrations of ropivacaine occurred at 37.5 minutes (range, 20\u0026ndash;60) after TAP block with a medium of 1.05 (range,0.50\u0026ndash;1.42), 1.36 (range, 0.72\u0026ndash;1.89), and 1.45 (range, 1.19\u0026ndash;2.06) \u0026micro;g mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e for each dose group (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Supplementary Figure \u003cb\u003eS4\u003c/b\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003ePlasma concentrations of lidocaine at all time points\u003c/h2\u003e \u003cp\u003eThe plasma lidocaine concentrations in the PP and ITT population were shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eD. Consistent concentration timings were found in both the PP and ITT patient populations. Most patients exhibited a peak plasma concentration at 10 minutes after the initial bolus intravenous infusion, with median peak concentrations of 4.59 (range, 3.24\u0026ndash;6.67) and 4.56 (range, 2.79\u0026ndash;7.16) \u0026micro;g mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e in the PP and ITT populations. The concentration dramatically dropped after 10 minutes post-bolus infusion and fluctuated between 1.68 and 4.22 \u0026micro;g mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e for up to 2 hours, then gradually decreased in the PP populations (Supplementary Figure S6). Among these patients, three in the PP population and eight in the ITT population had plasma concentrations exceeding the established toxicity threshold of 5.0 \u0026micro;g mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e at the 10 minutes timepoint (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Supplementary Figure S7).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study explored the dose-risk relationship of LAST associated with the combined use of a 0.2% ropivacaine TAP block, administered at escalating doses of 1.5, 2.0, and 2.5 mg kg⁻\u0026sup1;, alongside a 2% intravenous lidocaine infusion (2 mg kg⁻\u0026sup1; bolus, followed by continuous infusion at 2 mg kg⁻\u0026sup1; h⁻\u0026sup1;) in adult patients undergoing colorectal cancer surgery. Although no clinical symptoms of LAST were observed and ropivacaine plasma concentrations remained well below the established toxicity threshold, 8 out of 26 patients had plasma lidocaine concentrations exceeding 5.0 \u0026micro;g mL⁻\u0026sup1;. These findings suggest that while the combination of 1.5\u0026ndash;2.5 mg kg⁻\u0026sup1; ropivacaine TAP block and intravenous lidocaine infusion may not result in overt clinical manifestations of LAST, potential risks may still need to be considered.\u003c/p\u003e \u003cp\u003eColorectal cancer surgery is one of the most frequently performed surgical procedures worldwide, with approximately 1.2\u0026nbsp;million patients undergoing this surgery annually. Inadequate postoperative pain management not only impedes recovery but also increases the risk of chronic pain development, which significantly impacts the patient\u0026rsquo;s long-term quality of life [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Ropivacaine is commonly used in TAP blocks for abdominal surgeries, due to its favorable pharmacological profile, including reduced motor blockade, lower cardiotoxicity, and extended analgesia duration[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Unlike previous reports of neurotoxic symptoms such as tongue paresthesia, metallic taste, and slurred speech in patients receiving 2.5 mg kg⁻\u0026sup1; ropivacaine TAP blocks during cesarean sections [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], our study did not observe any signs of LAST. The discrepancy may be partly due to the ideal body weight other than actual body weight for dose calculations in our study, which helps mitigate the risk of overdose [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Additionally, we observed a dose-dependent increase in ropivacaine plasma concentration, with the 2.5 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e group exhibiting higher median levels compared to the two lower dose groups. A consistent time-concentration relationship was also noted, with peak plasma concentrations occurring between 20 and 60minutes post-TAP block, regardless of the total dose. This is consistent with the findings of Toju et al., who reported similar timing of peak concentrations following a 3 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e ropivacaine TAP block [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Given the stable pharmacokinetic profile of ropivacaine TAP blocks across dosages ranging from 1.5 to 3.0 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, it appears that the peak plasma concentration period may require enhanced monitoring and management, particularly at higher doses, to minimize the potential for toxic effects.\u003c/p\u003e \u003cp\u003eIn this study, although some patients exhibited plasma lidocaine concentrations exceeding the commonly cited neurologic toxicity threshold of 5.0 \u0026micro;g mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], no LAST events were reported. This observation is consistent with findings by Suena et al., who reported no correlation between plasma lidocaine levels above 5.0 \u0026micro;g mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e and LAST occurrence [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. The variability in lidocaine toxicity thresholds, ranging from 5.0 to 15 \u0026micro;g mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], indicates a broader spectrum of safe plasma levels [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], possibly influenced by patient-specific factors such as gender, comorbidities, and physiological characteristics [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Notably, the toxicity thresholds established for single-drug use may not be appropriate when these drugs are combined. Although ropivacaine is primarily bound to albumin and lidocaine binds to α-1 acid glycoprotein (AGP), the two drugs may exhibit overlapping binding at the F1*S site of AGP[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. This overlap could potentially elevate the free fraction of both drugs, thereby increasing the risk of LAST. Furthermore, the concurrent use of general anesthetics might alter the threshold for LAST threshold[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], adding further complexity to this clinical scenario.\u003c/p\u003e \u003cp\u003eNonetheless, our study represents a pioneering effort in evaluating the risk of concurrent administration of escalating doses of ropivacaine for TAP block and intravenous lidocaine infusion in patients undergoing colorectal surgery. This investigation highlights that careful attention to the potential risk of LAST is still warranted when using the two local anesthetics in combination. A key strength of our study was the implementation of EEG monitoring during general anaesthesia, which may help to detect potential neurotoxicity of local anaesthetics. Previous research has demonstrated that the plasma concentration threshold for lidocaine\u0026rsquo;s neurotoxicity (15 \u0026micro;g mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) is lower than that for cardiovascular toxicity (21 \u0026micro;g mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Therefore, relying solely on ECG monitoring during general anaesthesia may underestimate its toxicity. Combining the EEG and ECG may offer a more comprehensive approach to detecting LAST under general anaesthesia. Moreover, the precise in local anaesthetic administration achieved through ultrasound guidance by experienced anaesthesiologists further minimized the risk of inadvertent leakage into the surrounding musculature, which can affect drug absorption and increase the risk of toxicity [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Rosenberg et al. have recommended tailoring local anaesthetic dosage based on technique specificity rather than a maximum safe dose [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur study also acknowledged several limitations. Firstly, the small sample size, while a limitation, was a necessary consequence of adhering to the 3\u0026thinsp;+\u0026thinsp;3 dose-escalation trial design. Given the undefined toxicity risks associated with the combined use of the two local anesthetics, a minimal-risk exposure strategy was adopted to prioritize patient safety. As a result, the sample size was limited, preventing the ability to draw definitive conclusions about safety. Secondly, we cannot assess the analgesic efficacy due to the small sample size. While the dose levels for ropivacaine and lidocaine were selected based on existing studies reporting their effectiveness for postoperative pain relief in various surgical settings, either alone or in combination [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], it remains uncertain whether higher doses of ropivacaine would offer superior analgesia. Thirdly, we did not measure the unbound (free) concentration of ropivacaine or lidocaine. The toxicity of local anesthetics, however, is primarily determined by the free fraction of the drug, which represents the pharmacologically active component, rather than the total plasma concentration, this limits our ability to assess toxicity accurately. Finally, the toxicity levels referenced for intravenous lidocaine and ropivacaine TAP block were based on the established safety thresholds for each drug when used individually; however, these thresholds may not be suitable when the drugs are combined. The lack of a universally accepted toxicity threshold for their combined use presents a significant challenge in evaluating their safety. Future studies are needed to define safe thresholds and establish more precise guidelines for their combined use.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eAlthough no signs of LAST were observed with the combination of a 1.5 to 2.5 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e ropivacaine TAP block and a fixed-rate intravenous lidocaine infusion, caution is strongly advised regarding the risk of LAST when using this combination. Safe thresholds for the combined use of these local anesthetics have not yet been established, underscoring the need for further studies to define these limits more accurately.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eTAP: Transversus abdominis plane; LAST: Local anesthetic systemic toxicity; MTD: Maximum tolerated dose; ASA: Society of Anaesthesiologists; ECG: Electrocardiography; EEG: Electroencephalography; PSI: Patient State Index; PACU: Post-anaesthesia care unit; IBW: Ideal body weight; SD: Standard deviation; IQR: Interquartile range; PP: Per-protocol; ITT: Intention-to-treat; CONSORT: Consolidated Standards of Reporting Trials\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLi Zhou, Lulong Bo and Chunling Jiang: these authors helped to design the study and revise the manuscript; Mengmeng Zhou, Yan Xu: these authors helped to analyse and intepretate data; Xiaoting Hao: this author helped to analyse electroencephalogram.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFeng Yu, Jingwen Wu, Lajing Luowu, Qianqian Tang, Kun Shao, Mao Ye: these authors helped to collect date; All authors helped to draft the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by Sichuan Science and Technology Program [grant number 2023ZYD0168], Wu JiePing Medical Foundation [grant number 320.6750.2022-05-3].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted in accordance with the Declaration of Helsinki. Ethical approval was obtained from the Ethics Committee of West China Hospital, Sichuan University (approval number HX20201180-1). All patients provided informed consent and was enrolled after registration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003e Department of Anaesthesiology, West China Hospital, Sichuan University \u0026amp; The Research Units of West China (2018RU012), Chinese Academy of Medical Sciences, Chengdu, China.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e2\u0026nbsp;\u003c/sup\u003eDepartment of Neurology, West China Hospital, Sichuan University, Chengdu, China.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e3\u003c/sup\u003eDepartment of Anaesthesiology, Xinxiang Central Hospital, Xinxiang, China.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e4\u003c/sup\u003eFaculty of Anaesthesiology, Changhai Hospital, Naval Medical University, Shanghai, China.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGan TJ. Poorly controlled postoperative pain: prevalence, consequences, and prevention. J Pain Res 2017; 10: 2287-2298.\u003c/li\u003e\n\u003cli\u003eHyland SJ, Wetshtein AM, Grable SJ, Jackson MP. Acute Pain Management Pearls: A Focused Review for the Hospital Clinician. Healthcare (Basel) 2022; 11.\u003c/li\u003e\n\u003cli\u003eZhu QQ, Qu L, Su T et al. Risk Factors of Acute Pain in Elderly Patients After Laparoscopic Radical Resection of Colorectal Cancer. Surg Laparosc Endosc Percutan Tech 2024; 34: 43-47.\u003c/li\u003e\n\u003cli\u003eIrani JL, Hedrick TL, Miller TE et al. Clinical practice guidelines for enhanced recovery after colon and rectal surgery from the American Society of Colon and Rectal Surgeons and the Society of American Gastrointestinal and Endoscopic Surgeons. Surg Endosc 2023; 37: 5-30.\u003c/li\u003e\n\u003cli\u003eLiu T, Yang J, Wang Y et al. Interfascial plane block: a new anesthetic technique. Anesthesiol Periop Sci 2023; 1: 31.\u003c/li\u003e\n\u003cli\u003eTran DQ, Bravo D, Leurcharusmee P, Neal JM. Transversus Abdominis Plane Block: A Narrative Review. Anesthesiology 2019; 131: 1166-1190.\u003c/li\u003e\n\u003cli\u003ePeltrini R, Cantoni V, Green R et al. Efficacy of transversus abdominis plane (TAP) block in colorectal surgery: a systematic review and meta-analysis. Tech Coloproctol 2020; 24: 787-802.\u003c/li\u003e\n\u003cli\u003eXu Y, Ye M, Liu F et al. Efficacy of prolonged intravenous lidocaine infusion for postoperative movement-evoked pain following hepatectomy: a double-blinded, randomised, placebo-controlled trial. Br J Anaesth 2023; 131: 113-121.\u003c/li\u003e\n\u003cli\u003eYang W, Yan S, Yu F, Jiang C. Appropriate Duration of Perioperative Intravenous Administration of Lidocaine to Provide Satisfactory Analgesia for Adult Patients Undergoing Colorectal Surgery: A Meta-Analysis of Randomized Controlled Trials. Anesth Analg 2023; 136: 494-506.\u003c/li\u003e\n\u003cli\u003eFoo I, Macfarlane AJR, Srivastava D et al. The use of intravenous lidocaine for postoperative pain and recovery: international consensus statement on efficacy and safety. Anaesthesia 2021; 76: 238-250.\u003c/li\u003e\n\u003cli\u003eBailey MA, Toner AJ, Corcoran TB. A survey of perioperative intravenous lidocaine use by anaesthetists in Australia and New Zealand. Anaesth Intensive Care 2020; 48: 53-58.\u003c/li\u003e\n\u003cli\u003eMcDonnell JG, Curley G, Carney J et al. The analgesic efficacy of transversus abdominis plane block after cesarean delivery: a randomized controlled trial. Anesth Analg 2008; 106: 186-191.\u003c/li\u003e\n\u003cli\u003eGriffiths JD, Le NV, Grant S et al. Symptomatic local anaesthetic toxicity and plasma ropivacaine concentrations after transversus abdominis plane block for Caesarean section. Br J Anaesth 2013; 110: 996-1000.\u003c/li\u003e\n\u003cli\u003eBeaussier M, Delbos A, Maurice-Szamburski A et al. Perioperative Use of Intravenous Lidocaine. Drugs 2018; 78: 1229-1246.\u003c/li\u003e\n\u003cli\u003eYang S, Wang SJ, Ji Y. An integrated dose-finding tool for phase I trials in oncology. Contemp Clin Trials 2015; 45: 426-434.\u003c/li\u003e\n\u003cli\u003eEagleman SL, Drover CM, Li X et al. Offline comparison of processed electroencephalogram monitors for anaesthetic-induced electroencephalogram changes in older adults. Br J Anaesth 2021; 126: 975-984.\u003c/li\u003e\n\u003cli\u003eYurttas T, Djurdjevic M, Schnider TW, Filipovic M. Analgesic efficacy of systemic lidocaine using lean body mass based dosing regime versus placebo in bariatric surgery: a prospective, randomised, double-blind, placebo-controlled, single-centre study. Br J Anaesth 2023; 131: 122-129.\u003c/li\u003e\n\u003cli\u003eGriffiths JD, Barron FA, Grant S et al. Plasma ropivacaine concentrations after ultrasound-guided transversus abdominis plane block. Br J Anaesth 2010; 105: 853-856.\u003c/li\u003e\n\u003cli\u003eEl-Boghdadly K, Pawa A, Chin KJ. Local anesthetic systemic toxicity: current perspectives. Local Reg Anesth 2018; 11: 35-44.\u003c/li\u003e\n\u003cli\u003eKaplan PW. The EEG of status epilepticus. J Clin Neurophysiol 2006; 23: 221-229.\u003c/li\u003e\n\u003cli\u003eSpitzer D, Wenger KJ, Neef V et al. Local Anesthetic-Induced Central Nervous System Toxicity during Interscalene Brachial Plexus Block: A Case Series Study of Three Patients. J Clin Med 2021; 10.\u003c/li\u003e\n\u003cli\u003eNoachtar S, R\u0026eacute;mi J. The role of EEG in epilepsy: a critical review. Epilepsy Behav 2009; 15: 22-33.\u003c/li\u003e\n\u003cli\u003eQin WW, Jiao Z, Zhong MK et al. Simultaneous determination of procaine, lidocaine, ropivacaine, tetracaine and bupivacaine in human plasma by high-performance liquid chromatography. J Chromatogr B Analyt Technol Biomed Life Sci 2010; 878: 1185-1189.\u003c/li\u003e\n\u003cli\u003eScott DB, Lee A, Fagan D et al. Acute toxicity of ropivacaine compared with that of bupivacaine. Anesth Analg 1989; 69: 563-569.\u003c/li\u003e\n\u003cli\u003eKurzrock R, Lin CC, Wu TC et al. Moving Beyond 3+3: The Future of Clinical Trial Design. Am Soc Clin Oncol Educ Book 2021; 41: e133-e144.\u003c/li\u003e\n\u003cli\u003eLindberg M, Franklin O, Svensson J, Franklin KA. Postoperative pain after colorectal surgery. Int J Colorectal Dis 2020; 35: 1265-1272.\u003c/li\u003e\n\u003cli\u003ePing C, Lin QS, Lin XZ. Optimal concentration of the transversus abdominis plane block in enhanced recovery after surgery protocols for patients of advanced age undergoing laparoscopic rectal cancer surgery. J Int Med Res 2018; 46: 4437-4446.\u003c/li\u003e\n\u003cli\u003eToju K, Shiraishi K, Hakozaki T et al. Plasma ropivacaine concentration following ultrasound-guided subcostal transversus abdominis plane block in adults. J Anesth 2015; 29: 146-148.\u003c/li\u003e\n\u003cli\u003eFoldes FF, Molloy R, Mc NP, Koukal LR. Comparison of toxicity of intravenously given local anesthetic agents in man. J Am Med Assoc 1960; 172: 1493-1498.\u003c/li\u003e\n\u003cli\u003eSucena M, Cachapuz I, Lombardia E et al. Plasma concentration of lidocaine during bronchoscopy. Rev Port Pneumol 2004; 10: 287-296.\u003c/li\u003e\n\u003cli\u003eDeToledo JC. Lidocaine and seizures. Ther Drug Monit 2000; 22: 320-322.\u003c/li\u003e\n\u003cli\u003eBromage PR, Robson JG. Concentrations of lignocaine in the blood after intravenous, intramuscular epidural and endotracheal administration. Anaesthesia 1961; 16: 461-478.\u003c/li\u003e\n\u003cli\u003eMacfarlane AJR, Gitman M, Bornstein KJ et al. Updates in our understanding of local anaesthetic systemic toxicity: a narrative review. Anaesthesia 2021; 76 Suppl 1: 27-39.\u003c/li\u003e\n\u003cli\u003eMiller RJ, Cameron AJ, Dimech J et al. Plasma Ropivacaine Concentrations Following Local Infiltration Analgesia in Total Knee Arthroplasty: A Pharmacokinetic Study to Determine Safety Following Fixed-Dose Administration. Reg Anesth Pain Med 2018; 43: 347-351.\u003c/li\u003e\n\u003cli\u003eTaheri S, Cogswell LP, 3rd, Gent A, Strichartz GR. Hydrophobic and ionic factors in the binding of local anesthetics to the major variant of human alpha1-acid glycoprotein. J Pharmacol Exp Ther 2003; 304: 71-80.\u003c/li\u003e\n\u003cli\u003eDougherty PM, Raja SN. Chapter 2 - Neurochemist ry of Somatosensory and Pain Processing. In Benzon HT, Raja SN, Molloy RE et al. (eds): Essentials of Pain Medicine and Regional Anesthesia (Second Edition). Philadelphia: Churchill Livingstone 2005; 7-14.\u003c/li\u003e\n\u003cli\u003eWeinberg L, Peake B, Tan C, Nikfarjam MJWJoA. Pharmacokinetics and pharmacodynamics of lignocaine: A review. 2015; 4: 17-29.\u003c/li\u003e\n\u003cli\u003eKato N, Fujiwara Y, Harato M et al. Serum concentration of lidocaine after transversus abdominis plane block. J Anesth 2009; 23: 298-300.\u003c/li\u003e\n\u003cli\u003eRosenberg PH, Veering BT, Urmey WF. Maximum recommended doses of local anesthetics: a multifactorial concept. Reg Anesth Pain Med 2004; 29: 564-575; discussion 524.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-anesthesiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bane","sideBox":"Learn more about [BMC Anesthesiology](http://bmcanesthesiol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bane","title":"BMC Anesthesiology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-5690114/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5690114/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe concurrent use of a ropivacaine transversus abdominis plane (TAP) block with intravenous lidocaine infusion, though effective for pain relief, raises safety concerns regarding local anesthetic systemic toxicity (LAST). This study aimed to assess the dose-risk relationship of LAST in this combination by escalating the ropivacaine dose while fixing the lidocaine dose.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn this dose-escalation study, adult patients undergoing colorectal cancer surgery received a 0.2% ropivacaine TAP block (1.5, 2.0 or 2.5 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) and intravenous lidocaine infusion (2 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e bolus, followed by 2 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e h\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e), both dosed according to ideal body weight (IBW). The primary outcome was the occurrence of LAST, identified by clinical symptoms, new-onset ECG irregularities, etc. Secondary outcomes included plasma concentrations of ropivacaine and lidocaine.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eNine patients were included in the per-protocol analysis, and 26 were included in the intention-to-treat analysis. No signs of LAST were observed. Plasma ropivacaine concentrations remained consistently below 2.2 \u0026micro;g mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, however, eight patients in the intention-to-treat population and three patients in the per-protocol population had plasma lidocaine concentrations exceeding 5.0 \u0026micro;g mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e at 10 minutes post-bolus. In the per-protocol population, peak plasma ropivacaine concentrations occurred 30 minutes (range, 20\u0026ndash;60) post-TAP block, with median values of 1.14 (range, 0.85\u0026ndash;1.18), 1.42 (range, 1.29\u0026ndash;1.80), and 1.96 (range, 1.47\u0026ndash;2.06) \u0026micro;g mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e across dose groups. The peak plasma lidocaine concentrations in patients occurred at 10 minutes post-bolus infusion, with median values of 4.59 \u0026micro;g mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (range, 3.24\u0026ndash;6.67) and gradually decreased after 2 hours. The intention-to-treat analysis found similar results.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eAlthough no signs of LAST were observed with the combination of a 1.5 to 2.5 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e ropivacaine TAP block and intravenous lidocaine infusion under general anaesthesia, extreme caution is still warranted regarding the potential risk of LAST.\u003c/p\u003e","manuscriptTitle":"Combining ropivacaine transversus abdominis plane block with intravenous lidocaine infusion in adults undergoing colorectal cancer surgery: an open-label, dose-escalation exploratory trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-27 04:12:19","doi":"10.21203/rs.3.rs-5690114/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-06-09T14:56:04+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-05T07:57:11+00:00","index":"","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-25T14:43:38+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-25T14:16:39+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Anesthesiology","date":"2025-03-22T04:09:31+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-anesthesiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bane","sideBox":"Learn more about [BMC Anesthesiology](http://bmcanesthesiol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bane","title":"BMC Anesthesiology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9282b1ba-e8eb-4dba-a38e-155655e52c54","owner":[],"postedDate":"March 27th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-07-28T16:05:24+00:00","versionOfRecord":{"articleIdentity":"rs-5690114","link":"https://doi.org/10.1186/s12871-025-03225-5","journal":{"identity":"bmc-anesthesiology","isVorOnly":false,"title":"BMC Anesthesiology"},"publishedOn":"2025-07-22 15:57:37","publishedOnDateReadable":"July 22nd, 2025"},"versionCreatedAt":"2025-03-27 04:12:19","video":"","vorDoi":"10.1186/s12871-025-03225-5","vorDoiUrl":"https://doi.org/10.1186/s12871-025-03225-5","workflowStages":[]},"version":"v1","identity":"rs-5690114","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5690114","identity":"rs-5690114","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}