Anti-inflammatory Effect and Plasma Bupivacaine Concentrations After Transversus Abdominis Plane Block for Living Liver Donors: Prospective, Randomized, Blinded Clinical Trial

Anti-inflammatory Effect and Plasma Bupivacaine Concentrations After Transversus Abdominis Plane Block for Living Liver Donors: Prospective, Randomized, Blinded Clinical 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 Anti-inflammatory Effect and Plasma Bupivacaine Concentrations After Transversus Abdominis Plane Block for Living Liver Donors: Prospective, Randomized, Blinded Clinical Trial Mehmet Rıdvan Yalin, Mehmet Ali Erdogan, Muharrem Ucar, Muhammed Mehdi Uremis, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4322701/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective Transversus abdominis plane (TAP) blocks were reported to reduce postoperative pain and opioid use. Local anesthetics modulate the local and systemic inflammatory reaction. Our aim was to examine the effect of TAP block with bupivacaine on the anti-inflammatory response in living liver donors (LLDs). Methods The randomized prospective clinical study was carried out 72 LLDs, aged 18–65 scheduled for right hepatectomy. TAP blocks were performed bilaterally with ultrasound guidance using 1.5 mg/kg of 0.5% bupivacaine for Group 2. Group 1 patients were control group. In both groups, blood samples were obtained preoperatively, 30 minutes and 2, 6, and 24 hours following injection for cytokine measurement. In Group 2, to examine the plasma bupivacaine level, blood samples were obtained preoperatively as well as 30 minutes and 1, 2, 6, 12, and 24 hours following injection. The primary outcome was to assess the effect of TAP block on the inflammatory response with cytokine levels. Results No difference was observed between cytokine levels (Tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1) and interleukin 6 (IL-6) between Groups Significant positive correlations were observed between the plasma bupivacaine concentration and IL-1 and IL-6 levels at the 2nd, 6th and 24th hours Conclusions TAP block had no effect on the plasma cytokine concentration. Significant positive correlations were noted between the plasma bupivacaine concentration and IL-1 and IL-6 levels. Living liver donor TAP block abdominal Citokine Bupivacaine Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction A shortage of organ supply for adults with end-stage liver disease has caused an increase in the use of living donor liver transplantation. Living liver donors (LLDs) are healthy individuals and have the expectation of fast recovery with reduced postoperative pain after anesthesia and surgery [ 1 ]. The use of transversus abdominis plane (TAP) block as a part of multimodal analgesia in postoperative analgesia reduces perioperative and postoperative opioid consumption, provides shorter recovery time and shortens hospital stay in LLDs [ 2 , 3 ]. Tissue damage occurring during surgery and pain in the perioperative and postoperative periods has immunological metabolic and endocrine consequences. As the severity of these reactions increases, it causes an increased risk of surgical site infection, disturbances in wound healing prcess, systemic inflammatory response syndrome and dysfunction in multiple organ systems in the patients. Experimental studies have demonstrated that local anesthetics (LAs) and regional blocks modulate the regional and systemic inflammatory response that occur as result of surgical trauma [ 4 ]. Following surgical procedures, cytokines play an important role in the modulation of important processes such as local and systemic inflammation and hyperalgesia. Overwhelming dominance of either proinflammatory or anti-inflammatory cytokines has detrimental effect on the well-being of the host [ 5 ]. Tumor necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1) are the two main inducers of interleukin 6 (IL-6), which is produced from almost all cells and tissues, including the intestine. Following injury, circulating IL-6 levels can be detected in 60 minutes, peak levels are achieved between the 4th and 6th hours and continue for 10 days. Measurements of postoperative plasma concentrations of proinflammatory (TNF-α, IL-6, IL-1β, and IL-2) and anti-inflammatory (IL-1ra, IL-4, IL-10, and IL-13) cytokines help the determination of the severity systemic inflammatory response in the patients. Especially, IL-6 concentrations have a linear correlation with the severity of surgery and may predict postoperative prognosis of full recovery of the patients. Postoperative pain and proinflammatory cytokines are reduced with various applications including epidural anesthesia, peripheral nerve blocks and thoracic epidural anesthesia [ 6 – 8 ]. The efficacy of TAP blockade in promoting anti-inflammatory response in LLDs has not been reported. The aim of our study is to evaluate the efficacy of subcostal TAP block with bupivacaine in inducing the anti-inflammatory response in LLDs. Methods This randomized prospective clinical study was performed after approval from the institutional review board of Inonu University (Malatya Clinical Research Ethics Committee, 2017/128) that the protocols conformed to the ethical guidelines of the 1975 Helsinki Declaration was obtained. Written consent was obtained from all donors, and the study was registered prior to patient enrolment at ClinicalTrials.gov (NCT04232904, https://classic.clinicaltrials.gov/ct2/show/NCT04232904 , date of registration: 18 January 2020). The clinic trial was carried out at Inonu University Liver Transplant Institute, Malatya, Turkey. Seventy-two LLDs aged between 18–65 years, with American Society of Anesthesiologists (ASA) score I-II scheduled for right hepatectomy were included in the study. The donors participating in our study were relatives with their recipients and the relationship degree was a first- or second-degree relationship. Donors with systemic disease (such as diabetes and hypertension), recent (one week prior to the donor hepatectomy) opioid or nonsteroidal anti-inflammatory drug use, disturbaces in coagulation, history of allergy to the study drugs, previous chronic use of anticonvulsants such as pregabalin and/or gabapentin, and refusal to participate were excluded. Donors were randomly assigned based on a web-based randomization generation to Group 1(the control group) received standard general anesthesia or the intervention group with subcostal TAP blocks (Group 2). The present study was designed as a single-blind trial in which the researchers who administered the intervention and collected the data blinded for the treatment groups. No sedatives or premedications were administered. Donors were monitored with bispectral index (BIS) and electrocardiography, pulse oximeter, noninvasive blood pressure, and body temperature. Peripheral venous access was performed, and blood samples were obtained for preoperative cytokine and bupivacaine measurements. After preoxygenation, anesthesia was induced with 2–3 mg kg − 1 propofol and 1 mcg kg − 1 fentanyl. Neuromuscular blockage was achieved with 0.6 mg kg − 1 rocuronium. Anesthesia was maintained with desflurane, 0.25–0.5 mcg kg − 1 min − 1 remifentanil infusion, and an O2/air mixture. Desflurane at 0.6 and 1 MAC (minimum alveolar concentration) was used to keep the BIS value in a range of 40 to 60. After anesthesia induction, an arterial line (radial artery) was established all donors to collect blood samples during the study and monitor invasive arterial blood pressure during surgery. All subcostal TAP blocks were performed following induction and immediately before the surgical incision by the same experienced anesthesiologist. The subcostal TAP block was applied bilaterally with real-time ultrasonography (LOGIQ S8, GE Ultrasound, Korea) guidance with a linear 6–13 MHz probe with a 22-G 80-mm needle (Stimuplex Ultra 360 B. Braun Aesculao Japan Co. Ltd. Japan) using the in-plane technique in the subcostal region as previously described [ 3 , 4 ]. A total of 1.5 mg/kg 0.5% bupivacaine (in 2 syringes with 20 mL bupivacaine + saline) was applied to the abdominal wall bilaterally. In both groups, blood samples were obtained preoperatively, 30 minutes and 2, 6, and 24 hours following injection for cytokine measurement. In Group 1, to examine the plasma bupivacaine level, blood samples were obtained preoperatively as well as 30 minutes and 1, 2, 6, 12, and 24 hours following injection. Signs of toxicity of the central nervous and cardiovascular systems, including perioral numbness, metallic taste, dizziness, tingling sensation, muscle twitch, disorders of speech and convulsions were regularly checked in the post-operative period. Postoperative analgesia management of the all patients was provided by a patient-controlled analgesia device with morphine (90 mL of SF with 10 mL of morphine sulfate [100 mg]), the locking time of the device was adjusted for 15 minutes and an intermittent bolus of 2 mg. The primary outcome was to examine the efficacy of subcostal TAP block in reducing the inflammatory response in the treatment arm of the study. Secondary outcomes included plasma bupivacaine concentrations and the correlation between plasma bupivacaine levels and cytokine levels in just the intervention group. Whole blood samples drawn from the patients were centrifuged at 4000 rpm for 7 minutes, and their serum was separated. The samples were separated in to aliquots and kept in a -80°C until the analyses. Analysis of blood samples Serum IL-1β, IL-6 and TNF-α levels were evaluated by enzyme-linked immunosorbent assay (ELISA) kits (YLBiont, Shanghai, China). The ELISA kit was evaluated spectrophotometric analysis using 595 nm UV in microplate reader (BioTek Synergy H1, BioTek Instruments) in accordance with the kit procedure. The concentration values ​​of the samples were determined from the standard curve based on absorbances using the data analysis program (Gen5, BioTek Instruments), and the values ​​were drawn with the help of known standards. The determination of bupivacaine in serum can be performed by several methods including high-performance liquid chromatography (HPLC), GC-MS, capillary electrophoresis and LC-MS [ 9 , 10 ]. We chose HPLC foe determination of serum bupivacaine because post-elimination doses of the drug required measurement with a highly sensitive test that was minimally affected by other factors such drugs that are administered concomitantly. Reagents and materials Standard for bupivacaine was obtained from Sigma-Aldrich (Germany). The pure bupivacaine standard was weighed accurately, and a 1.00 mg L − 1 stock standard solution was prepared by dissolving in 10 mL acetonitrile and water (75:25 v/v). A calibration curve was prepared with five points in the range of 0.1 to 100 mg mL − 1 by diluting the stock standard solution with acetonitrile and water (75:25, v/v). The calibration curve is used to calculate the samples of the treatment and the control arm of the study. Instrumentation Chromatographic qualitative and quantitative analyses of bupivacaine were performed on a Shimadzu chromatography system. This system contains a photodiode array (PDA) detector. All analyses were performed via a Shimadzu HPLC equipped with a Shimadzu DGU-20 A5 model vacuum degasser and a Shimadzu 20 ADXR solvent pump. Separations were performed through an ODS-2, C18 (150 mm × 4.6 mm, 3 µm) column at room temperature and at 207 nm (Fig. 1 ). Bupivacaine measurements were performed using the optimum separation conditions by HPLC with gradient elution and a flow rate of 1.0 ml min − 1 . The mobile phase included of solvent A (0.03 M sodium dihydrogen phosphate solution) and solvent B (acetonitrile 100%). The following linear gradient was used: at 0 min, 85% solvent A and 15% solvent B; between 3–15 min, 40% solvent A and 60% solvent B; in 15 minutes, 85% solvent A and 15% solvent B; and in 20 minutes, return to initial conditions. Sample preparation procedure Plasma bupivacaine concentrations were determined using HPLC using the methodology described by Purvis et al. and Faura et al. [ 11 – 13 ]. Acetonitrile (500 µL) was added to the plasma sample (1 ml) in the tube, and tubes were screwed on and mixed by vortexing for 5 min. The tubes were centrifuged for approximately 10 min at 5000 rpm. The extract was injected into the HPLC system after it was filtered through a membrane filter (0.22-µm PVDF). Discrete chromatograms were observed. Peaks were spate from one and other without any interference. The bupivacaine chromatography results are summarized in Fig. 1 . Statistical analyses All statistical analyses were performed using Statistical Software Package for Social Sciences software package version 22 (SPSS v22) (IBM, New York, ABD. Shapiro Wilk test was used to determine the normal distribution of the continuous data. Continuous data were analyzed using independent samples t test or Mann-Whitney U test. Categorical data were analyzed using the chi-square or Yates corrected chi-square test, depending on the situation. Differences between repeated measurements were analyzed using the Friedman test. Correlations between different variables were analyzed with the Spearman correlation coefficient. Data are presented as medians ± quartiles or means and standard deviations, and categorical data are presented as numbers and percentages. Α p-value < 0.05 was considered significant for all analyses. Based on IL-6 values in a previous study, when the amount of type I error (alpha) is 0.05, the power of the test (1-beta) is 0.8 [ 14 ]. Thus, it was determined that a minimum sample size of 34 individuals with 17 in each group is required to observe a 20% difference in the IL-6 mean values with an effect size of 1.01 (large). The power analysis was performed using Web-Based Sample Size & Power Analysis Software (WSSPAS) [ 15 ]. Results Seventy-eight LLDs were included to our study. Six of the patients were excluded, 4 were excluded because they did not meet the inclusion criteria or they did or want to participate in the study. In the remaining two patients, surgical complications developed . Total of 72 LLDs were analyzed, 37 were in Group 1 and 35 in Group 2 (Figure 2.) The demographic characteristics of the study groups were comparable (Table 1.). Serum bupivacaine concentration changes in time summarized in Figure 3. The peak bupivacaine concentration was 1.666 µg/ml, which was obtained in the second hour after injection. Individual bupivacaine concentration changes in time are summarized in Figure 3. Individual peak plasma concentration was 4.195 µg/ml, which was observed in the 2 nd hour measurement. The peak plasma bupivacaine concentration occurred at the 2-h measurement in 15 individuals, at the one-hour measurement in 10 individuals, at the 30-min measurement in 6 individuals, and at the 6-hour measurement in 4 individuals. No difference was observed between cytokine levels (IL-1, IL-6 and TNF) between Groups 1 and 2 (Figure 4.). When the relationship between plasma bupivacaine concentrations and simultaneous cytokine levels were analyzed, significant positive correlations were observed between the plasma bupivacaine concentration and IL-1 and IL-6 levels in the samples taken in 2 nd , 6 th and 24 th hours (Table 2.). Blood pressure and heart rate did not change and no signs of cardiovascular or central nervous system toxicity developed in any patients Discussion Subcostal TAP block with bupivacaine performed on LLDs who underwent right hepatectomy had no effect on the metabolic, endocrine and inflammatory response to surgical trauma based on plasma cytokine concentration. Surgical trauma causes the release of proinflammatory and anti-inflammatory proteins, which leads to an inflammatory response. Proinflammatory cytokines are localized at the injury site and cause undesirable systemic effects leading to increased heart rate, tachypnea, elevated white blood cell counts and fever. Treatments causing a blunted inflammatory response can provide counterbalance by reducing proinflammatory response caused by injury and may help functional recovery [ 16 ]. Chemokines, including IL-6 and IL-8, can cause prolonged hyperalgesia and indirectly regulate pain by altering pain signal transduction through the release of cytokine-induced neuroactive substances [ 17 ]. It was reported that plasma IL-6 concentration increased at 2–4 h in all patients in a study evaluating different types of surgery, including minor surgery, cholecystectomy, hip replacement, surgery for colorectal diseases, and major interventions such as cardiovascular surgery [ 18 ]. In a systematic review including a total of 103 studies (n = 4,192), the IL-6 concentration was associated with the magnitude and invasiveness of the surgical procedure [ 19 ]. Our study results of the peak time and peak value of IL-6 concentration are similar to those reported in these studies. Rettg et al. [ 20 ] showed that postoperative IL-6 levels exceeding 432 pg/mL in the first postoperative day are associated with an increased postoperative complication risk and a longer hospital stay after elective major abdominal surgery. It was emphasized that the optimal cutoff level of IL-6 for the prediction of complications is between 300 and 400 pg/mL on postoperative first day with a low specificity (70%) and sensitivity (64%) [ 20 ]. In our literature review, we did not encounter any study examining the values of cytokine levels in LLDs. In the present study, the IL-6 value was below the cutoff level of 432 pg/mL on postoperative first day, and no complications were observed. Proinflammatory stimuli primarily regulates the phagocytic functions of leukocytes and the secretion of lysosomal enzymes and various inflammatory mediators. Various clinical and experimental studies have shown that LAs reversibly suppress leukocyte to blood vessel walls in a dose-dependent manner [ 4 ]. When peripheral nerve blocks with LAs were performed on the contralateral limb, the nerve block could reduce both paw hyperalgesia and edema created with local tissue inflammation. This finding may explain the anti-inflammatory effect of absorption of Las [ 21 ]. However, systemic administration of bupivacaine had no effect on hyperalgesia or local inflammation [ 22 ]. Previous studies have shown that nerve blocks, such as epidural analgesia, attenuate proinflammatory cytokines [ 7 , 21 – 24 ]. In the present study, there was no effect of subcostal TAP blockade on plasma cytokine concentrations. The probable reasons depend on several factors, such as the technique of regional anesthesia, the type and invasiveness of surgery, method used to measure cytokine concentrations and the type of marker. The correlation between cytokine levels and bupivacaine concentrations has not been previously assessed with TAP block (a peripheral nerve block). We found a positive correlation between cytokine levels and bupivacaine concentrations which was statistically significant. In our opinion, these plasma bupivacaine concentrations is not associated with reduced or attenuated production of cytokines (IL-6 and IL-1). Our study is unique because it is the first prospective study to analyze plasma bupivacaine concentrations in LLDs following TAP block. In the present study, the peak bupivacaine concentration occurred in all individuals in the 1st-2nd hours. Additionally, the mean peak total bupivacaine concentration was achieved in the 2nd hour following injection, which is different from other studies that performed TAP block [ 13 , 25 – 27 ]. This difference may be attributed to the different surgical procedure in our study. Right hepatectomy, which entails removal of approximately two-thirds of the liver, was used in our study. Large-scale hepatectomy may change bupivacaine metabolism [ 28 ]. The steady-state distribution of LAs volume increases with liver dysfunction. In this case, the LAs dose should be reduced as metabolites accumulate with repeated doses or continuous infusion administration. However, the α-1 acid glycoprotein is synthesized even in end-stage liver failure and is protective against LAs toxicity. There are more important indicators, such as nephropathy and heart disease, to reduce the LAs doses in patients with severe liver dysfunction [ 29 ]. In this study, the doses recommended in previous TAP block studies were used without reduction, because of that repeated or continuous infusion of LAs was not used, our patients had no systemic dysfunction before surgery, and the incision of the liver parenchyma was performed after the 60th minute of the operation [ 2 , 3 , 25 ]. In addition, it has been reported that LAs can be safely administered generally with normal doses (total bupivacaine dose varies between 1.05 and 1.69 mg/kg, and the recommended maximum dose is 2 mg/kg) as a single dose block in patients with hepatic dysfunction [ 30 ]. This clinical study has some limitations. First, tissue edema, discoloration, circumference, skin temperature, and tissue cytokine levels in the surgical area were not measured. Covering the surgical area in the perioperative period prevented these assays. Second, plasma cytokine concentrations were not evaluated until the 1st week postoperatively. However, this study was designed on the correlation between perioperative bupivacaine levels and cytokine levels. The superior aspects of this study were as follows. All surgeries were performed with the same surgical techniques, and the study was performed in a homogeneous group with healthy individuals. Conclusion Subcostal TAP block with bupivacaine applied in LLDs who underwent right hepatectomy had no effect on the plasma cytokine concentration. Significant positive correlations were noted between the plasma bupivacaine concentration and IL-1 and IL-6 levels at 2, 6 and 24 h. In addition, in this study, plasma bupivacaine concentrations within 24 hours after TAP block were determined in LLDs. Abbreviations TAP Transversus abdominis plane LLDs Living liver donors TNF-α Tumor necrosis factor-alpha IL-1 Interleukin-1 IL-6 Interleukin 6 LAs Local anesthetics ASA American Society of Anesthesiologists BIS Bispectral index ELISA Enzyme-linked immunosorbent assay HPLC High-performance liquid chromatography Declarations Acknowledgments We would like to thank Dr. Mahmut Durmus for his assistance with the study. Ethics approval and consent to participate This clinical study was permitted by the Local Ethics Committee of Inonu University Medical Faculty, Malatya, Turkey. Authors confirm that all experiments were performed in accordance with relevant guidelines and regulations. Authors confirm that informed consent was obtained from all donors and/or their legal guardian(s). Consent for publication Not Applicable Data availability The datasets generated and/or analyzed during the current case report are not publicly available, but are available from the corresponding author on reasonable request. Conflict of interest The authors declare that they do not have any conflict of interest. Funding Funding for the present study was supported by Inonu University Scientific Research Projects Coordination Unit with project number 2018-911 for drug supply with bupivacaine and cytokines analiz Author contributions MRY: Study design, patient recruitment, data collection; MAE: Study design, interpretation and critical revision of the manuscript; MU: Data collection and writing up of the first draft of the paper; MME: Samples analysis;YZÇ: Data analysis and interpretation; EO:patient recruitment, data collection; UO: Drafting of the manuscript; SE: Data and sample analysis; CC: Statistical analysis; YU: Data and sample analysis OK: Drafting of the manuscript; HIT References Trevor LN, Reddy MS, Elizabeth AP, Rela M. Progression of living liver donation worldwide. Curr Opin Organ Transpl. 2018;23(2):162–8. 10.1097/MOT.0000000000000516 . Erdogan MA, Ozgul U, Uçar M, Yalin R, Colak YZ, et al. Effect of transversus abdominis plane block in combination with general anesthesia on perioperative opioid consumption, hemodynamics, and recovery in living liver donors: The prospective, double-blinded, randomized study. Clin Transpl. 2017;31(4). 10.1111/ctr.12931 . Kıtlık A, Erdogan MA, Ozgul U, Aydogan MS, Ucar M, et al. Ultrasound-guided transversus abdominis plane block for postoperative analgesia in living liver donors: A prospective, randomized, double-blinded clinical trial. J Clin Anesth. 2017;37:103–7. 10.1016/j.jclinane.2016.12.018 . Cassuto J, Sinclair R, Bonderovic M. Anti-inflammatory properties of local anesthetics and their present and potential clinical implications. Acta Anaesthesiol Scand. 2006;50(3):265–82. 10.1111/j.1399-6576.2006.00936.x . Yardeni IZ, Beilin B, Mayburd E, Levinson Y, Bessler H. The Effect of Perioperative Intravenous Lidocaine on Postoperative Pain and Immune Function. Anesth Analg. 2009;109(5):1464–9. 10.1213/ANE.0b013e3181bab1bd . Combettes E, Benhamou D, Mazoit JX. Comparison of a bupivacaine peripheral nerve block and systemic ketoprofen on peripheral inflammation and hyperalgesia in rats. Eur J Anaesthesiol. 2010;27(7):642–7. 10.1097/eja.0b013e3283366590 . Bagry H, de la Cuadra Fontaine JC, Asenjo JF, Bracco D, Carli F. Effect of a continuous peripheral nerve block on the inflammatory response in knee arthroplasty. Reg Anesth Pain Med. 2008;33(1):17–23. 10.1016/j.rapm.2007.06.398 . Kuo CP, Jao SW, Chen KM, Wong CS, Yeh CC, et al. Comparison of the effects of thoracic epidural analgesia and i.v. infusion with lidocaine on cytokine response, postoperative pain and bowel function in patients undergoing colonic surgery. Br J Anaesth. 2006;97(5):640–6. 10.1093/bja/ael217 . Qin WW, Jiao Z, Zhong MK, Shi XJ, Zhang J, et al. Simultaneous determination of procaine, lidocaine, ropivacaine, tetracaine and bupivacaine in human plasma by high-performance liquid chromatography. J Chromatogr B. 2010;878(15–16):1185–9. 10.1016/j.jchromb.2010.03.003 . Daryanavard SM, Jeppsson-Dadoun A, Andersson LI, Hashemi M, Colmsjö A, et al. Molecularly imprinted polymer in microextraction by packed sorbent for the simultaneous determination of local anesthetics: lidocaine, ropivacaine, mepivacaine and bupivacaine in plasma and urine samples. Biomed Chromatogr. 2013;27(11):1481–8. 10.1002/bmc.2946 . Faura A, Modamio P, Blanco D, Segarra I, Lastra CF, et al. Is the pharmacokinetics of bupivacaine equivalent after lumbar epidural administration through a needle or a catheter in male and female adults? Biomed Pharmacother. 2015;70:119–22. 10.1016/j.biopha.2015.01.003 . Purvis T. Simultaneous High Performance Liquid Chromatography Assay of Pentoxifylline, Bupivacaine HCl, Levocetirizine HCl, Tranilast, and Fluticasone Propionate in Humco™ Sanare Advanced Scar Base. Separations. 2016;3(2):15. 10.3390/separations3020015 . Suresh S, De Oliveira GS. Blood bupivacaine concentrations after transversus abdominis plane block in neonates: a prospective observational study. Anesth Analg. 2016;122(3):814–7. 10.1213/ANE.0000000000001088 . Martin F, Martinez V, Mazoit JX, Bouhassira D, Cherif K, et al. Antiinflammatory effect of peripheral nerve blocks after knee surgery: clinical and biologic evaluation. Anesthesiology. 2008;109(3):484–90. 10.1097/ALN.0b013e318182c2a1 . Arslan AK, Yasar S, Colak C, Yologlu S. WSSPAS: An Interactive Web Application for Sample Size and Power Analysis with R Using Shiny. Turkiye Klinikleri J Biostatistics. 2018;10(3):224–46. 10.5336/biostatic.2018-62787 . Munford RS, Pugin J. Normal responses to injury prevent systemic inflammation and can be immuno-suppressive. Am J Respir Crit Care Med. 2001;163(2):316–21. 10.1164/ajrccm.163.2.2007102 . Watkins LR, Milligan ED, Maier SF. Glial proinflammatory cytokines mediate exaggerated pain states: implications for clinical pain. Adv Exp Med Biol. 2003;521:1–21. Cruickshank AM, Fraser WD, Burns HJ, Damme JV, Shenkin A. Response of serum interleukin-6 in patients undergoing elective surgery of varying severity. Clin Sci (Lond). 1990;79(82):161–5. 10.1042/cs0790161 . Watt DG, Horgan PG, McMillan DC. Routine clinical markers of the magnitude of the systemic inflammatory response after elective operation: a systematic review. Surgery. 2015;157(2):362–80. 10.1016/j.surg.2014.09.009 . Rettig TC, Verwijmeren L, Dijkstra IM, Boerma D, van de Garde EM, Noordzij PG. Postoperative Interleukin-6 Level and Early Detection of Complications After Elective Major Abdominal Surgery. Ann Surg. 2016;263(6):1207–12. 10.1097/SLA.0000000000001342 . Irina G, Lavand’homme P. Continuous regional anesthesia and inflammation: a new target. Minerva Anestesiol. 2015;81(9):1001–9. Beloeil H, Gentili M, Benhamou D, Mazoit JX. The effect of a peripheral block on inflammation-induced prostaglandin E2 and cyclooxygenase expression in rats. Anesth Analg. 2009;109(3):943–50. 10.1213/ane.0b013e3181aff25e . Baker EA, El-Gaddal S, Williams L, Leaper DJ. Profiles of inflammatory cytokines following colorectal surgery: relationship with wound healing and outcome. Wound Repair Regen. 2006;14(5):566–72. 10.1111/j.1743-6109.2006.00163.x . Moselli NM, Baricocchi E, Ribero D, Sottile A, Suita L, Debernardi F. Intraoperative epidural analgesia prevents the early proinflammatory response to surgical trauma. Results from a prospective randomized clinical trial of intraoperative epidural versus general analgesia. Ann Surg Oncol. 2011;18(10):2722–31. 10.1245/s10434-011-1700-9 . Trabelsi B, Charfi R, Bennasr L, Marzouk SB, Eljebari H, et al. Pharmacokinetics of bupivacaine after bilateral ultrasound-guided transversus abdominis plane block following cesarean delivery under spinal anesthesia. Int J Obstet Anesth. 2017;32:17–20. 10.1016/j.ijoa.2017.04.007 . Griffiths JD, Barron FA, Grant S, Bjorksten AR, Hebbard P, Royseet CF. Plasma ropivacaine concentrations after ultrasound-guided transversus abdominis plane block. Br J Anaesth. 2010;105(6):853–6. 10.1093/bja/aeq255 . Griffiths JD, Le NV, Grant S, Hebbard P, Royse C. Symptomatic local anaesthetic toxicity and plasma ropivacaine concentrations after transversus abdominis plane block for Caesarean section. Br J Anaesth. 2013;110(6):996–1000. 10.1093/bja/aet015 . Yokoyama M, Mizobuchi S, Nagano OH, Fujii Yamashita M, Hirakawa M. The effects of epidural insertion site and surgical procedure on plasma lidocaine concentration. Anesth Analg. 2001;92(2):470–5. 10.1097/00000539-200102000-00036 . Jokinen M. Effects of drug interactions and liver disease on the pharmacokinetics of ropivacaine.Helsinki,2003. https://helda.helsinki.fi/bitstream/handle/10138/22557/effectso.pdf?sequence=2 . accessed 10 September 2019. Rosenberg PH, Veering BT, Urmey WF. Maximum recommended doses of local anesthetics: a multifactorial concept. Reg Anesth Pain Med. 2004;29(6):564–75. 10.1016/j.rapm.2004.08.003 . Tables Table 1. The demographic data of the patients. Group Mean (SD) P value Age (years) 1 29,16 7,104 0,811 2 29,57 7,326 Height (cm) 1 172,05 8,592 0,344 2 173,91 7,950 Weight (kg) 1 71,81 10,651 0,738 2 72,71 12,140 Operation time (min) 1 384,16 68,545 0,260 2 403,09 72,867 Blood loss (mL) 1 279,46 107,003 0,565 2 294,57 114,567 Urine output (mL) 1 892,16 261,875 0,282 2 800,57 437,425 SD=standard deviation. Table 2. The relationship between plasma bupivacaine concentrations and simultaneous cytokine levels. Time Bupivacaine Cytokine levels Spearman's rho P Value 30 min 1.519 ± 0.919 IL-1 29,295 ± 28,686 0,111 0,558 IL-6 127,599 ± 90,454 0,182 0,335 TNF 86,411 ± 69,592 0,101 0,595 2 hour 1,664 ± 0,787 IL-1 44,532± 42,613 0,529 0,003* IL-6 120,324 ± 111,081 0,577 0,001* TNF 99,153 ± 84,655 0,274 0,143 6 hour 1,335 ± 0,508 IL-1 35,078 ± 43,01 0,424 0,02* IL-6 134,565 ± 122,227 0,463 0,011* TNF 68,725 ± 69,918 0,342 0,065 24 hour 0,864 ± 0,295 IL-1 37,869 ± 45,628 0,443 0,014* IL-6 108,746 ± 122,972 0,41 0,025* TNF 70,159 ± 79,274 0,294 0,114 Values are presented as mean ± standard deviation. *= p-value ≤ 0.05 is statistically significant Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-4322701","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":311027880,"identity":"4a5e3641-4653-425b-a8be-5404865d04a2","order_by":0,"name":"Mehmet Rıdvan Yalin","email":"","orcid":"","institution":"Inonu University","correspondingAuthor":false,"prefix":"","firstName":"Mehmet","middleName":"Rıdvan","lastName":"Yalin","suffix":""},{"id":311027881,"identity":"3c51fc5d-9640-49e9-bd7e-0dca467d4b1d","order_by":1,"name":"Mehmet Ali Erdogan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9klEQVRIiWNgGAWjYDCCA0D8wADKYKgAYmbmBsJaEuBazoC0MBKjBcZgbAOxCGjhu3068UNCgU0+3/H2i58L59VG87cDtfyo2IZTi+S53M0SCQZpljPPnCmWnrnteO6Mw4wNjD1nbuPUYnCGdwNQy2EDgxs5CdK8247lNgC1MDO24dWy+UeCwX+QluTfvHOO5c4nQss2oC0HgFrSj0nzNtTkbiCkRRKoxSLBINlA8swZNmueYwdyNwK1HMTnFz6gw258+GNnAAyxx7d5aupy550/fPDBjwrcWpAADyhCD4OZB4hRDwTsD4BEHZGKR8EoGAWjYCQBAFM3YvITMuV2AAAAAElFTkSuQmCC","orcid":"","institution":"Inonu University","correspondingAuthor":true,"prefix":"","firstName":"Mehmet","middleName":"Ali","lastName":"Erdogan","suffix":""},{"id":311027882,"identity":"ab23c389-4689-4cd0-ba1b-263827a704f2","order_by":2,"name":"Muharrem Ucar","email":"","orcid":"","institution":"Inonu University","correspondingAuthor":false,"prefix":"","firstName":"Muharrem","middleName":"","lastName":"Ucar","suffix":""},{"id":311027883,"identity":"52d6a30d-df27-4c9d-9b84-9a624ab389d6","order_by":3,"name":"Muhammed Mehdi Uremis","email":"","orcid":"","institution":"Inonu University","correspondingAuthor":false,"prefix":"","firstName":"Muhammed","middleName":"Mehdi","lastName":"Uremis","suffix":""},{"id":311027884,"identity":"418e57f5-a150-4caf-893f-a3669c49f28f","order_by":4,"name":"Yusuf Ziya Colak","email":"","orcid":"","institution":"Inonu University","correspondingAuthor":false,"prefix":"","firstName":"Yusuf","middleName":"Ziya","lastName":"Colak","suffix":""},{"id":311027885,"identity":"546c21de-b7ac-42cb-beb5-827440c7dfd6","order_by":5,"name":"Emine Ozdemir","email":"","orcid":"","institution":"Inonu University","correspondingAuthor":false,"prefix":"","firstName":"Emine","middleName":"","lastName":"Ozdemir","suffix":""},{"id":311027886,"identity":"d64ade49-7b11-4db7-bbbe-0fc1ca5cc40d","order_by":6,"name":"Yılmaz Ugur","email":"","orcid":"","institution":"Inonu University","correspondingAuthor":false,"prefix":"","firstName":"Yılmaz","middleName":"","lastName":"Ugur","suffix":""},{"id":311027887,"identity":"24173eca-21b1-4af9-9c08-474ad9cc8c58","order_by":7,"name":"Ulku Ozgul","email":"","orcid":"","institution":"Inonu University","correspondingAuthor":false,"prefix":"","firstName":"Ulku","middleName":"","lastName":"Ozgul","suffix":""},{"id":311027888,"identity":"c31aafc9-1ec8-4888-9edd-fdead2ae7399","order_by":8,"name":"Selim Erdogan","email":"","orcid":"","institution":"Inonu University","correspondingAuthor":false,"prefix":"","firstName":"Selim","middleName":"","lastName":"Erdogan","suffix":""},{"id":311027889,"identity":"316934cf-54d4-410d-9b4b-977572986d07","order_by":9,"name":"Osman Kacmaz","email":"","orcid":"","institution":"Inonu University","correspondingAuthor":false,"prefix":"","firstName":"Osman","middleName":"","lastName":"Kacmaz","suffix":""},{"id":311027890,"identity":"c11cd7e7-d7c9-438d-b753-3902b3bea828","order_by":10,"name":"Cemil Colak","email":"","orcid":"","institution":"Inonu University","correspondingAuthor":false,"prefix":"","firstName":"Cemil","middleName":"","lastName":"Colak","suffix":""},{"id":311027893,"identity":"d34a8aa2-114c-4a6e-800e-16aa809d37f6","order_by":11,"name":"Huseyin İlksen Toprak","email":"","orcid":"","institution":"Inonu University","correspondingAuthor":false,"prefix":"","firstName":"Huseyin","middleName":"İlksen","lastName":"Toprak","suffix":""}],"badges":[],"createdAt":"2024-04-25 08:32:30","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4322701/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4322701/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":58144075,"identity":"ade97234-6a45-47d7-884c-28b02961ecb0","added_by":"auto","created_at":"2024-06-11 18:23:00","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":8653592,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4322701/v1/2cdf32473d3d493b7af041dc.png"},{"id":58145367,"identity":"dad664f1-eec9-4694-ab15-9102456145c4","added_by":"auto","created_at":"2024-06-11 18:31:00","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":2959801,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4322701/v1/d7b1d55c155291ff6565cc18.png"},{"id":58144072,"identity":"dd44d9d7-eec4-45e2-866c-ca3850bc90bd","added_by":"auto","created_at":"2024-06-11 18:23:00","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":2268707,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-4322701/v1/6a5ed7cbb0c1f2c0dbd660a7.png"},{"id":58144074,"identity":"977ab984-7b68-40e2-a613-fee8131a09f6","added_by":"auto","created_at":"2024-06-11 18:23:00","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":3303710,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-4322701/v1/a73a6339050ab9724fd06cb5.png"},{"id":59508542,"identity":"fa8d13ca-c6e6-4d54-9bf6-167c925b7816","added_by":"auto","created_at":"2024-07-02 15:47:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":25600488,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4322701/v1/fa4e4032-6ab3-4bf6-9f03-240819d53c66.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Anti-inflammatory Effect and Plasma Bupivacaine Concentrations After Transversus Abdominis Plane Block for Living Liver Donors: Prospective, Randomized, Blinded Clinical Trial","fulltext":[{"header":"Introduction","content":"\u003cp\u003eA shortage of organ supply for adults with end-stage liver disease has caused an increase in the use of living donor liver transplantation. Living liver donors (LLDs) are healthy individuals and have the expectation of fast recovery with reduced postoperative pain after anesthesia and surgery [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe use of transversus abdominis plane (TAP) block as a part of multimodal analgesia in postoperative analgesia reduces perioperative and postoperative opioid consumption, provides shorter recovery time and shortens hospital stay in LLDs [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTissue damage occurring during surgery and pain in the perioperative and postoperative periods has immunological metabolic and endocrine consequences. As the severity of these reactions increases, it causes an increased risk of surgical site infection, disturbances in wound healing prcess, systemic inflammatory response syndrome and dysfunction in multiple organ systems in the patients. Experimental studies have demonstrated that local anesthetics (LAs) and regional blocks modulate the regional and systemic inflammatory response that occur as result of surgical trauma [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFollowing surgical procedures, cytokines play an important role in the modulation of important processes such as local and systemic inflammation and hyperalgesia. Overwhelming dominance of either proinflammatory or anti-inflammatory cytokines has detrimental effect on the well-being of the host [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Tumor necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1) are the two main inducers of interleukin 6 (IL-6), which is produced from almost all cells and tissues, including the intestine. Following injury, circulating IL-6 levels can be detected in 60 minutes, peak levels are achieved between the 4th and 6th hours and continue for 10 days. Measurements of postoperative plasma concentrations of proinflammatory (TNF-α, IL-6, IL-1β, and IL-2) and anti-inflammatory (IL-1ra, IL-4, IL-10, and IL-13) cytokines help the determination of the severity systemic inflammatory response in the patients. Especially, IL-6 concentrations have a linear correlation with the severity of surgery and may predict postoperative prognosis of full recovery of the patients. Postoperative pain and proinflammatory cytokines are reduced with various applications including epidural anesthesia, peripheral nerve blocks and thoracic epidural anesthesia [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The efficacy of TAP blockade in promoting anti-inflammatory response in LLDs has not been reported.\u003c/p\u003e \u003cp\u003eThe aim of our study is to evaluate the efficacy of subcostal TAP block with bupivacaine in inducing the anti-inflammatory response in LLDs.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e This randomized prospective clinical study was performed after approval from the institutional review board of Inonu University (Malatya Clinical Research Ethics Committee, 2017/128) that the protocols conformed to the ethical guidelines of the 1975 Helsinki Declaration was obtained. Written consent was obtained from all donors, and the study was registered prior to patient enrolment at ClinicalTrials.gov (NCT04232904, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://classic.clinicaltrials.gov/ct2/show/NCT04232904\u003c/span\u003e\u003cspan address=\"https://classic.clinicaltrials.gov/ct2/show/NCT04232904\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e, date of registration: 18 January 2020). The clinic trial was carried out at Inonu University Liver Transplant Institute, Malatya, Turkey. Seventy-two LLDs aged between 18\u0026ndash;65 years, with American Society of Anesthesiologists (ASA) score I-II scheduled for right hepatectomy were included in the study. The donors participating in our study were relatives with their recipients and the relationship degree was a first- or second-degree relationship. Donors with systemic disease (such as diabetes and hypertension), recent (one week prior to the donor hepatectomy) opioid or nonsteroidal anti-inflammatory drug use, disturbaces in coagulation, history of allergy to the study drugs, previous chronic use of anticonvulsants such as pregabalin and/or gabapentin, and refusal to participate were excluded.\u003c/p\u003e \u003cp\u003eDonors were randomly assigned based on a web-based randomization generation to Group 1(the control group) received standard general anesthesia or the intervention group with subcostal TAP blocks (Group 2). The present study was designed as a single-blind trial in which the researchers who administered the intervention and collected the data blinded for the treatment groups.\u003c/p\u003e \u003cp\u003eNo sedatives or premedications were administered. Donors were monitored with bispectral index (BIS) and electrocardiography, pulse oximeter, noninvasive blood pressure, and body temperature. Peripheral venous access was performed, and blood samples were obtained for preoperative cytokine and bupivacaine measurements. After preoxygenation, anesthesia was induced with 2\u0026ndash;3 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e propofol and 1 mcg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e fentanyl. Neuromuscular blockage was achieved with 0.6 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e rocuronium. Anesthesia was maintained with desflurane, 0.25\u0026ndash;0.5 mcg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e remifentanil infusion, and an O2/air mixture. Desflurane at 0.6 and 1 MAC (minimum alveolar concentration) was used to keep the BIS value in a range of 40 to 60. After anesthesia induction, an arterial line (radial artery) was established all donors to collect blood samples during the study and monitor invasive arterial blood pressure during surgery.\u003c/p\u003e \u003cp\u003eAll subcostal TAP blocks were performed following induction and immediately before the surgical incision by the same experienced anesthesiologist. The subcostal TAP block was applied bilaterally with real-time ultrasonography (LOGIQ S8, GE Ultrasound, Korea) guidance with a linear 6\u0026ndash;13 MHz probe with a 22-G 80-mm needle (Stimuplex Ultra 360 B. Braun Aesculao Japan Co. Ltd. Japan) using the in-plane technique in the subcostal region as previously described [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. A total of 1.5 mg/kg 0.5% bupivacaine (in 2 syringes with 20 mL bupivacaine\u0026thinsp;+\u0026thinsp;saline) was applied to the abdominal wall bilaterally.\u003c/p\u003e \u003cp\u003eIn both groups, blood samples were obtained preoperatively, 30 minutes and 2, 6, and 24 hours following injection for cytokine measurement. In Group 1, to examine the plasma bupivacaine level, blood samples were obtained preoperatively as well as 30 minutes and 1, 2, 6, 12, and 24 hours following injection.\u003c/p\u003e \u003cp\u003eSigns of toxicity of the central nervous and cardiovascular systems, including perioral numbness, metallic taste, dizziness, tingling sensation, muscle twitch, disorders of speech and convulsions were regularly checked in the post-operative period. Postoperative analgesia management of the all patients was provided by a patient-controlled analgesia device with morphine (90 mL of SF with 10 mL of morphine sulfate [100 mg]), the locking time of the device was adjusted for 15 minutes and an intermittent bolus of 2 mg.\u003c/p\u003e \u003cp\u003eThe primary outcome was to examine the efficacy of subcostal TAP block in reducing the inflammatory response in the treatment arm of the study. Secondary outcomes included plasma bupivacaine concentrations and the correlation between plasma bupivacaine levels and cytokine levels in just the intervention group.\u003c/p\u003e \u003cp\u003eWhole blood samples drawn from the patients were centrifuged at 4000 rpm for 7 minutes, and their serum was separated. The samples were separated in to aliquots and kept in a -80\u0026deg;C until the analyses.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eAnalysis of blood samples\u003c/h2\u003e \u003cp\u003eSerum IL-1β, IL-6 and TNF-α levels were evaluated by enzyme-linked immunosorbent assay (ELISA) kits (YLBiont, Shanghai, China). The ELISA kit was evaluated spectrophotometric analysis using 595 nm UV in microplate reader (BioTek Synergy H1, BioTek Instruments) in accordance with the kit procedure. The concentration values ​​of the samples were determined from the standard curve based on absorbances using the data analysis program (Gen5, BioTek Instruments), and the values ​​were drawn with the help of known standards.\u003c/p\u003e \u003cp\u003eThe determination of bupivacaine in serum can be performed by several methods including high-performance liquid chromatography (HPLC), GC-MS, capillary electrophoresis and LC-MS [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe chose HPLC foe determination of serum bupivacaine because post-elimination doses of the drug required measurement with a highly sensitive test that was minimally affected by other factors such drugs that are administered concomitantly.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eReagents and materials\u003c/h2\u003e \u003cp\u003eStandard for bupivacaine was obtained from Sigma-Aldrich (Germany). The pure bupivacaine standard was weighed accurately, and a 1.00 mg L\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e stock standard solution was prepared by dissolving in 10 mL acetonitrile and water (75:25 v/v). A calibration curve was prepared with five points in the range of 0.1 to 100 mg mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e by diluting the stock standard solution with acetonitrile and water (75:25, v/v). The calibration curve is used to calculate the samples of the treatment and the control arm of the study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eInstrumentation\u003c/h2\u003e \u003cp\u003eChromatographic qualitative and quantitative analyses of bupivacaine were performed on a Shimadzu chromatography system. This system contains a photodiode array (PDA) detector. All analyses were performed via a Shimadzu HPLC equipped with a Shimadzu DGU-20 A5 model vacuum degasser and a Shimadzu 20 ADXR solvent pump. Separations were performed through an ODS-2, C18 (150 mm \u0026times; 4.6 mm, 3 \u0026micro;m) column at room temperature and at 207 nm (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eBupivacaine measurements were performed using the optimum separation conditions by HPLC with gradient elution and a flow rate of 1.0 ml min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe mobile phase included of solvent A (0.03 M sodium dihydrogen phosphate solution) and solvent B (acetonitrile 100%). The following linear gradient was used: at 0 min, 85% solvent A and 15% solvent B; between 3\u0026ndash;15 min, 40% solvent A and 60% solvent B; in 15 minutes, 85% solvent A and 15% solvent B; and in 20 minutes, return to initial conditions.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eSample preparation procedure\u003c/h2\u003e \u003cp\u003ePlasma bupivacaine concentrations were determined using HPLC using the methodology described by Purvis et al. and Faura et al. [\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAcetonitrile (500 \u0026micro;L) was added to the plasma sample (1 ml) in the tube, and tubes were screwed on and mixed by vortexing for 5 min. The tubes were centrifuged for approximately 10 min at 5000 rpm. The extract was injected into the HPLC system after it was filtered through a membrane filter (0.22-\u0026micro;m PVDF).\u003c/p\u003e \u003cp\u003eDiscrete chromatograms were observed. Peaks were spate from one and other without any interference. The bupivacaine chromatography results are summarized in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eStatistical analyses\u003c/p\u003e \u003cp\u003eAll statistical analyses were performed using Statistical Software Package for Social Sciences software package version 22 (SPSS v22) (IBM, New York, ABD. Shapiro Wilk test was used to determine the normal distribution of the continuous data. Continuous data were analyzed using independent samples t test or Mann-Whitney U test. Categorical data were analyzed using the chi-square or Yates corrected chi-square test, depending on the situation. Differences between repeated measurements were analyzed using the Friedman test. Correlations between different variables were analyzed with the Spearman correlation coefficient. Data are presented as medians\u0026thinsp;\u0026plusmn;\u0026thinsp;quartiles or means and standard deviations, and categorical data are presented as numbers and percentages. Α p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered significant for all analyses. Based on IL-6 values in a previous study, when the amount of type I error (alpha) is 0.05, the power of the test (1-beta) is 0.8 [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Thus, it was determined that a minimum sample size of 34 individuals with 17 in each group is required to observe a 20% difference in the IL-6 mean values with an effect size of 1.01 (large). The power analysis was performed using Web-Based Sample Size \u0026amp; Power Analysis Software (WSSPAS) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eSeventy-eight LLDs were included to our study. Six of the patients were excluded, 4 were excluded because they did not meet the inclusion criteria or they did or want to participate in the study. In the remaining \u0026nbsp;two patients, surgical complications developed . Total of 72 \u0026nbsp; LLDs were analyzed, 37 were in Group 1 and 35 in Group 2 (Figure 2.) The demographic characteristics of the study groups were comparable (Table 1.).\u003c/p\u003e\n\u003cp\u003eSerum bupivacaine concentration changes in time summarized in Figure 3. The peak bupivacaine concentration was 1.666 \u0026micro;g/ml, which was obtained in the second hour after injection. Individual bupivacaine concentration changes in time are summarized in Figure 3. Individual peak plasma concentration was 4.195 \u0026micro;g/ml, which was observed in the 2\u003csup\u003end\u003c/sup\u003e hour measurement. The peak plasma bupivacaine concentration\u0026nbsp;occurred\u0026nbsp;at\u0026nbsp;the\u0026nbsp;2-h measurement in 15 individuals, at\u0026nbsp;the\u0026nbsp;one-hour measurement in 10 individuals, at\u0026nbsp;the\u0026nbsp;30-min measurement in 6 individuals,\u0026nbsp;and\u0026nbsp;at\u0026nbsp;the\u0026nbsp;6-hour measurement in 4 individuals.\u003c/p\u003e\n\u003cp\u003eNo difference was observed between cytokine levels (IL-1, IL-6 and TNF)\u0026nbsp;between\u0026nbsp;Groups 1 and 2 (Figure 4.).\u003c/p\u003e\n\u003cp\u003eWhen the relationship between plasma bupivacaine concentrations and simultaneous cytokine levels were analyzed,\u0026nbsp;significant positive\u0026nbsp;correlations\u0026nbsp;were observed between the plasma bupivacaine concentration and IL-1 and IL-6 levels in the samples taken in\u0026nbsp;2\u003csup\u003end\u003c/sup\u003e,\u0026nbsp;6\u003csup\u003eth\u003c/sup\u003e and 24\u003csup\u003eth\u003c/sup\u003e hours\u0026nbsp;(Table 2.).\u003c/p\u003e\n\u003cp\u003eBlood pressure and heart rate did not change and no signs of cardiovascular or central nervous system toxicity developed in any patients\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eSubcostal TAP block with bupivacaine performed on LLDs who underwent right hepatectomy had no effect on the metabolic, endocrine and inflammatory response to surgical trauma based on plasma cytokine concentration.\u003c/p\u003e \u003cp\u003eSurgical trauma causes the release of proinflammatory and anti-inflammatory proteins, which leads to an inflammatory response. Proinflammatory cytokines are localized at the injury site and cause undesirable systemic effects leading to increased heart rate, tachypnea, elevated white blood cell counts and fever. Treatments causing a blunted inflammatory response can provide counterbalance by reducing proinflammatory response caused by injury and may help functional recovery [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Chemokines, including IL-6 and IL-8, can cause prolonged hyperalgesia and indirectly regulate pain by altering pain signal transduction through the release of cytokine-induced neuroactive substances [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIt was reported that plasma IL-6 concentration increased at 2\u0026ndash;4 h in all patients in a study evaluating different types of surgery, including minor surgery, cholecystectomy, hip replacement, surgery for colorectal diseases, and major interventions such as cardiovascular surgery [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In a systematic review including a total of 103 studies (n\u0026thinsp;=\u0026thinsp;4,192), the IL-6 concentration was associated with the magnitude and invasiveness of the surgical procedure [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Our study results of the peak time and peak value of IL-6 concentration are similar to those reported in these studies.\u003c/p\u003e \u003cp\u003eRettg et al. [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] showed that postoperative IL-6 levels exceeding 432 pg/mL in the first postoperative day are associated with an increased postoperative complication risk and a longer hospital stay after elective major abdominal surgery. It was emphasized that the optimal cutoff level of IL-6 for the prediction of complications is between 300 and 400 pg/mL on postoperative first day with a low specificity (70%) and sensitivity (64%) [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In our literature review, we did not encounter any study examining the values of cytokine levels in LLDs. In the present study, the IL-6 value was below the cutoff level of 432 pg/mL on postoperative first day, and no complications were observed.\u003c/p\u003e \u003cp\u003eProinflammatory stimuli primarily regulates the phagocytic functions of leukocytes and the secretion of lysosomal enzymes and various inflammatory mediators. Various clinical and experimental studies have shown that LAs reversibly suppress leukocyte to blood vessel walls in a dose-dependent manner [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWhen peripheral nerve blocks with LAs were performed on the contralateral limb, the nerve block could reduce both paw hyperalgesia and edema created with local tissue inflammation. This finding may explain the anti-inflammatory effect of absorption of Las [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. However, systemic administration of bupivacaine had no effect on hyperalgesia or local inflammation [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePrevious studies have shown that nerve blocks, such as epidural analgesia, attenuate proinflammatory cytokines [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan additionalcitationids=\"CR22 CR23\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. In the present study, there was no effect of subcostal TAP blockade on plasma cytokine concentrations. The probable reasons depend on several factors, such as the technique of regional anesthesia, the type and invasiveness of surgery, method used to measure cytokine concentrations and the type of marker. The correlation between cytokine levels and bupivacaine concentrations has not been previously assessed with TAP block (a peripheral nerve block). We found a positive correlation between cytokine levels and bupivacaine concentrations which was statistically significant. In our opinion, these plasma bupivacaine concentrations is not associated with reduced or attenuated production of cytokines (IL-6 and IL-1).\u003c/p\u003e \u003cp\u003eOur study is unique because it is the first prospective study to analyze plasma bupivacaine concentrations in LLDs following TAP block. In the present study, the peak bupivacaine concentration occurred in all individuals in the 1st-2nd hours. Additionally, the mean peak total bupivacaine concentration was achieved in the 2nd hour following injection, which is different from other studies that performed TAP block [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. This difference may be attributed to the different surgical procedure in our study. Right hepatectomy, which entails removal of approximately two-thirds of the liver, was used in our study. Large-scale hepatectomy may change bupivacaine metabolism [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe steady-state distribution of LAs volume increases with liver dysfunction. In this case, the LAs dose should be reduced as metabolites accumulate with repeated doses or continuous infusion administration. However, the α-1 acid glycoprotein is synthesized even in end-stage liver failure and is protective against LAs toxicity. There are more important indicators, such as nephropathy and heart disease, to reduce the LAs doses in patients with severe liver dysfunction [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. In this study, the doses recommended in previous TAP block studies were used without reduction, because of that repeated or continuous infusion of LAs was not used, our patients had no systemic dysfunction before surgery, and the incision of the liver parenchyma was performed after the 60th minute of the operation [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. In addition, it has been reported that LAs can be safely administered generally with normal doses (total bupivacaine dose varies between 1.05 and 1.69 mg/kg, and the recommended maximum dose is 2 mg/kg) as a single dose block in patients with hepatic dysfunction [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis clinical study has some limitations. First, tissue edema, discoloration, circumference, skin temperature, and tissue cytokine levels in the surgical area were not measured. Covering the surgical area in the perioperative period prevented these assays. Second, plasma cytokine concentrations were not evaluated until the 1st week postoperatively. However, this study was designed on the correlation between perioperative bupivacaine levels and cytokine levels.\u003c/p\u003e \u003cp\u003eThe superior aspects of this study were as follows. All surgeries were performed with the same surgical techniques, and the study was performed in a homogeneous group with healthy individuals.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eSubcostal TAP block with bupivacaine applied in LLDs who underwent right hepatectomy had no effect on the plasma cytokine concentration. Significant positive correlations were noted between the plasma bupivacaine concentration and IL-1 and IL-6 levels at 2, 6 and 24 h. In addition, in this study, plasma bupivacaine concentrations within 24 hours after TAP block were determined in LLDs.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eTAP Transversus abdominis plane \u003c/p\u003e\n\u003cp\u003eLLDs Living liver donors \u003c/p\u003e\n\u003cp\u003eTNF-\u0026alpha; Tumor necrosis factor-alpha\u003c/p\u003e\n\u003cp\u003eIL-1 Interleukin-1\u003c/p\u003e\n\u003cp\u003eIL-6 Interleukin 6\u003c/p\u003e\n\u003cp\u003eLAs Local anesthetics \u003c/p\u003e\n\u003cp\u003eASA American Society of Anesthesiologists\u003c/p\u003e\n\u003cp\u003eBIS Bispectral index\u003c/p\u003e\n\u003cp\u003eELISA Enzyme-linked immunosorbent assay\u003c/p\u003e\n\u003cp\u003eHPLC High-performance liquid chromatography \u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank Dr. Mahmut Durmus for his assistance with the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis clinical study was permitted by the Local Ethics Committee of Inonu University Medical Faculty, Malatya, Turkey.\u003c/p\u003e\n\u003cp\u003eAuthors confirm that all experiments were performed in accordance with relevant guidelines and regulations.\u003c/p\u003e\n\u003cp\u003eAuthors confirm that informed consent was obtained from all donors and/or their legal guardian(s).\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\u003eData availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the current case report are not publicly available, but are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they do not have any conflict of interest.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFunding for the present study was supported by Inonu University Scientific Research Projects Coordination Unit with project number 2018-911 for drug supply with bupivacaine and cytokines analiz\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMRY: Study design, patient recruitment, data collection; MAE: Study design, interpretation and critical revision of the manuscript; MU: Data collection and writing up of the first draft of the paper; MME: Samples analysis;YZ\u0026Ccedil;: Data analysis and interpretation; EO:patient recruitment, data collection; UO: Drafting of the manuscript; SE: Data and sample analysis; CC: Statistical analysis; YU: Data and sample analysis OK: Drafting of the manuscript; HIT\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eTrevor LN, Reddy MS, Elizabeth AP, Rela M. Progression of living liver donation worldwide. Curr Opin Organ Transpl. 2018;23(2):162\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/MOT.0000000000000516\u003c/span\u003e\u003cspan address=\"10.1097/MOT.0000000000000516\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eErdogan MA, Ozgul U, U\u0026ccedil;ar M, Yalin R, Colak YZ, et al. Effect of transversus abdominis plane block in combination with general anesthesia on perioperative opioid consumption, hemodynamics, and recovery in living liver donors: The prospective, double-blinded, randomized study. Clin Transpl. 2017;31(4). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/ctr.12931\u003c/span\u003e\u003cspan address=\"10.1111/ctr.12931\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKıtlık A, Erdogan MA, Ozgul U, Aydogan MS, Ucar M, et al. Ultrasound-guided transversus abdominis plane block for postoperative analgesia in living liver donors: A prospective, randomized, double-blinded clinical trial. J Clin Anesth. 2017;37:103\u0026ndash;7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jclinane.2016.12.018\u003c/span\u003e\u003cspan address=\"10.1016/j.jclinane.2016.12.018\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCassuto J, Sinclair R, Bonderovic M. Anti-inflammatory properties of local anesthetics and their present and potential clinical implications. Acta Anaesthesiol Scand. 2006;50(3):265\u0026ndash;82. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/j.1399-6576.2006.00936.x\u003c/span\u003e\u003cspan address=\"10.1111/j.1399-6576.2006.00936.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYardeni IZ, Beilin B, Mayburd E, Levinson Y, Bessler H. The Effect of Perioperative Intravenous Lidocaine on Postoperative Pain and Immune Function. Anesth Analg. 2009;109(5):1464\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1213/ANE.0b013e3181bab1bd\u003c/span\u003e\u003cspan address=\"10.1213/ANE.0b013e3181bab1bd\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCombettes E, Benhamou D, Mazoit JX. Comparison of a bupivacaine peripheral nerve block and systemic ketoprofen on peripheral inflammation and hyperalgesia in rats. Eur J Anaesthesiol. 2010;27(7):642\u0026ndash;7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/eja.0b013e3283366590\u003c/span\u003e\u003cspan address=\"10.1097/eja.0b013e3283366590\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBagry H, de la Cuadra Fontaine JC, Asenjo JF, Bracco D, Carli F. Effect of a continuous peripheral nerve block on the inflammatory response in knee arthroplasty. Reg Anesth Pain Med. 2008;33(1):17\u0026ndash;23. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.rapm.2007.06.398\u003c/span\u003e\u003cspan address=\"10.1016/j.rapm.2007.06.398\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKuo CP, Jao SW, Chen KM, Wong CS, Yeh CC, et al. Comparison of the effects of thoracic epidural analgesia and i.v. infusion with lidocaine on cytokine response, postoperative pain and bowel function in patients undergoing colonic surgery. Br J Anaesth. 2006;97(5):640\u0026ndash;6. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/bja/ael217\u003c/span\u003e\u003cspan address=\"10.1093/bja/ael217\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQin WW, Jiao Z, Zhong MK, Shi XJ, Zhang J, et al. Simultaneous determination of procaine, lidocaine, ropivacaine, tetracaine and bupivacaine in human plasma by high-performance liquid chromatography. J Chromatogr B. 2010;878(15\u0026ndash;16):1185\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jchromb.2010.03.003\u003c/span\u003e\u003cspan address=\"10.1016/j.jchromb.2010.03.003\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDaryanavard SM, Jeppsson-Dadoun A, Andersson LI, Hashemi M, Colmsj\u0026ouml; A, et al. Molecularly imprinted polymer in microextraction by packed sorbent for the simultaneous determination of local anesthetics: lidocaine, ropivacaine, mepivacaine and bupivacaine in plasma and urine samples. Biomed Chromatogr. 2013;27(11):1481\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/bmc.2946\u003c/span\u003e\u003cspan address=\"10.1002/bmc.2946\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFaura A, Modamio P, Blanco D, Segarra I, Lastra CF, et al. Is the pharmacokinetics of bupivacaine equivalent after lumbar epidural administration through a needle or a catheter in male and female adults? Biomed Pharmacother. 2015;70:119\u0026ndash;22. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.biopha.2015.01.003\u003c/span\u003e\u003cspan address=\"10.1016/j.biopha.2015.01.003\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePurvis T. Simultaneous High Performance Liquid Chromatography Assay of Pentoxifylline, Bupivacaine HCl, Levocetirizine HCl, Tranilast, and Fluticasone Propionate in Humco\u0026trade; Sanare Advanced Scar Base. Separations. 2016;3(2):15. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/separations3020015\u003c/span\u003e\u003cspan address=\"10.3390/separations3020015\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSuresh S, De Oliveira GS. Blood bupivacaine concentrations after transversus abdominis plane block in neonates: a prospective observational study. Anesth Analg. 2016;122(3):814\u0026ndash;7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1213/ANE.0000000000001088\u003c/span\u003e\u003cspan address=\"10.1213/ANE.0000000000001088\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMartin F, Martinez V, Mazoit JX, Bouhassira D, Cherif K, et al. Antiinflammatory effect of peripheral nerve blocks after knee surgery: clinical and biologic evaluation. Anesthesiology. 2008;109(3):484\u0026ndash;90. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/ALN.0b013e318182c2a1\u003c/span\u003e\u003cspan address=\"10.1097/ALN.0b013e318182c2a1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArslan AK, Yasar S, Colak C, Yologlu S. WSSPAS: An Interactive Web Application for Sample Size and Power Analysis with R Using Shiny. Turkiye Klinikleri J Biostatistics. 2018;10(3):224\u0026ndash;46. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.5336/biostatic.2018-62787\u003c/span\u003e\u003cspan address=\"10.5336/biostatic.2018-62787\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMunford RS, Pugin J. Normal responses to injury prevent systemic inflammation and can be immuno-suppressive. Am J Respir Crit Care Med. 2001;163(2):316\u0026ndash;21. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1164/ajrccm.163.2.2007102\u003c/span\u003e\u003cspan address=\"10.1164/ajrccm.163.2.2007102\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWatkins LR, Milligan ED, Maier SF. Glial proinflammatory cytokines mediate exaggerated pain states: implications for clinical pain. Adv Exp Med Biol. 2003;521:1\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCruickshank AM, Fraser WD, Burns HJ, Damme JV, Shenkin A. Response of serum interleukin-6 in patients undergoing elective surgery of varying severity. Clin Sci (Lond). 1990;79(82):161\u0026ndash;5. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1042/cs0790161\u003c/span\u003e\u003cspan address=\"10.1042/cs0790161\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWatt DG, Horgan PG, McMillan DC. Routine clinical markers of the magnitude of the systemic inflammatory response after elective operation: a systematic review. Surgery. 2015;157(2):362\u0026ndash;80. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.surg.2014.09.009\u003c/span\u003e\u003cspan address=\"10.1016/j.surg.2014.09.009\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRettig TC, Verwijmeren L, Dijkstra IM, Boerma D, van de Garde EM, Noordzij PG. Postoperative Interleukin-6 Level and Early Detection of Complications After Elective Major Abdominal Surgery. Ann Surg. 2016;263(6):1207\u0026ndash;12. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/SLA.0000000000001342\u003c/span\u003e\u003cspan address=\"10.1097/SLA.0000000000001342\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIrina G, Lavand\u0026rsquo;homme P. Continuous regional anesthesia and inflammation: a new target. Minerva Anestesiol. 2015;81(9):1001\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBeloeil H, Gentili M, Benhamou D, Mazoit JX. The effect of a peripheral block on inflammation-induced prostaglandin E2 and cyclooxygenase expression in rats. Anesth Analg. 2009;109(3):943\u0026ndash;50. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1213/ane.0b013e3181aff25e\u003c/span\u003e\u003cspan address=\"10.1213/ane.0b013e3181aff25e\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBaker EA, El-Gaddal S, Williams L, Leaper DJ. Profiles of inflammatory cytokines following colorectal surgery: relationship with wound healing and outcome. Wound Repair Regen. 2006;14(5):566\u0026ndash;72. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/j.1743-6109.2006.00163.x\u003c/span\u003e\u003cspan address=\"10.1111/j.1743-6109.2006.00163.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoselli NM, Baricocchi E, Ribero D, Sottile A, Suita L, Debernardi F. Intraoperative epidural analgesia prevents the early proinflammatory response to surgical trauma. Results from a prospective randomized clinical trial of intraoperative epidural versus general analgesia. Ann Surg Oncol. 2011;18(10):2722\u0026ndash;31. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1245/s10434-011-1700-9\u003c/span\u003e\u003cspan address=\"10.1245/s10434-011-1700-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTrabelsi B, Charfi R, Bennasr L, Marzouk SB, Eljebari H, et al. Pharmacokinetics of bupivacaine after bilateral ultrasound-guided transversus abdominis plane block following cesarean delivery under spinal anesthesia. Int J Obstet Anesth. 2017;32:17\u0026ndash;20. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ijoa.2017.04.007\u003c/span\u003e\u003cspan address=\"10.1016/j.ijoa.2017.04.007\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGriffiths JD, Barron FA, Grant S, Bjorksten AR, Hebbard P, Royseet CF. Plasma ropivacaine concentrations after ultrasound-guided transversus abdominis plane block. Br J Anaesth. 2010;105(6):853\u0026ndash;6. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/bja/aeq255\u003c/span\u003e\u003cspan address=\"10.1093/bja/aeq255\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGriffiths JD, Le NV, Grant S, Hebbard P, Royse C. Symptomatic local anaesthetic toxicity and plasma ropivacaine concentrations after transversus abdominis plane block for Caesarean section. Br J Anaesth. 2013;110(6):996\u0026ndash;1000. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/bja/aet015\u003c/span\u003e\u003cspan address=\"10.1093/bja/aet015\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYokoyama M, Mizobuchi S, Nagano OH, Fujii Yamashita M, Hirakawa M. The effects of epidural insertion site and surgical procedure on plasma lidocaine concentration. Anesth Analg. 2001;92(2):470\u0026ndash;5. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/00000539-200102000-00036\u003c/span\u003e\u003cspan address=\"10.1097/00000539-200102000-00036\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJokinen M. Effects of drug interactions and liver disease on the pharmacokinetics of ropivacaine.Helsinki,2003.\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://helda.helsinki.fi/bitstream/handle/10138/22557/effectso.pdf?sequence=2\u003c/span\u003e\u003cspan address=\"https://helda.helsinki.fi/bitstream/handle/10138/22557/effectso.pdf?sequence=2\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. accessed 10 September 2019.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRosenberg PH, Veering BT, Urmey WF. Maximum recommended doses of local anesthetics: a multifactorial concept. Reg Anesth Pain Med. 2004;29(6):564\u0026ndash;75. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.rapm.2004.08.003\u003c/span\u003e\u003cspan address=\"10.1016/j.rapm.2004.08.003\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. The demographic data of the patients.\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"533\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"18.913857677902623%\" valign=\"bottom\" style=\"width: 18.9493%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.112359550561798%\" valign=\"bottom\" style=\"width: 12.3827%;\"\u003e\n \u003cp\u003eGroup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.39325842696629%\" colspan=\"2\" valign=\"bottom\" style=\"width: 43.7148%;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.790262172284645%\" valign=\"bottom\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"18.878504672897197%\" rowspan=\"2\" style=\"width: 18.9493%;\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.093457943925234%\" valign=\"top\" style=\"width: 12.3827%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.757009345794394%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e29,16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.757009345794394%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e7,104\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.757009345794394%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e0,811\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.442396313364055%\" valign=\"top\" style=\"width: 12.3827%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.889400921658986%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e29,57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.889400921658986%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e7,326\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.889400921658986%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"18.878504672897197%\" rowspan=\"2\" style=\"width: 18.9493%;\"\u003e\n \u003cp\u003eHeight (cm)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.093457943925234%\" valign=\"top\" style=\"width: 12.3827%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.757009345794394%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e172,05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.757009345794394%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e8,592\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.757009345794394%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e0,344\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.442396313364055%\" valign=\"top\" style=\"width: 12.3827%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.889400921658986%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e173,91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.889400921658986%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e7,950\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.889400921658986%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"18.878504672897197%\" rowspan=\"2\" style=\"width: 18.9493%;\"\u003e\n \u003cp\u003eWeight (kg)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.093457943925234%\" valign=\"top\" style=\"width: 12.3827%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.757009345794394%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e71,81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.757009345794394%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e10,651\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.757009345794394%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e0,738\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.442396313364055%\" valign=\"top\" style=\"width: 12.3827%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.889400921658986%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e72,71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.889400921658986%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e12,140\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.889400921658986%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"18.878504672897197%\" rowspan=\"2\" style=\"width: 18.9493%;\"\u003e\n \u003cp\u003eOperation time (min)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.093457943925234%\" valign=\"top\" style=\"width: 12.3827%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.757009345794394%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e384,16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.757009345794394%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e68,545\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.757009345794394%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e0,260\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.442396313364055%\" valign=\"top\" style=\"width: 12.3827%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.889400921658986%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e403,09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.889400921658986%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e72,867\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.889400921658986%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"18.878504672897197%\" rowspan=\"2\" style=\"width: 18.9493%;\"\u003e\n \u003cp\u003eBlood loss (mL)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.093457943925234%\" valign=\"top\" style=\"width: 12.3827%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.757009345794394%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e279,46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.757009345794394%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e107,003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.757009345794394%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e0,565\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.442396313364055%\" valign=\"top\" style=\"width: 12.3827%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.889400921658986%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e294,57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.889400921658986%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e114,567\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.889400921658986%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"18.878504672897197%\" rowspan=\"2\" style=\"width: 18.9493%;\"\u003e\n \u003cp\u003eUrine output (mL)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.093457943925234%\" valign=\"top\" style=\"width: 12.3827%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.757009345794394%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e892,16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.757009345794394%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e261,875\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.757009345794394%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e0,282\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.442396313364055%\" valign=\"top\" style=\"width: 12.3827%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.889400921658986%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e800,57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.889400921658986%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e437,425\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.889400921658986%\" valign=\"top\" style=\"width: 21.7636%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eSD=standard deviation.\u003c/p\u003e\n\u003cp\u003eTable 2. The relationship between plasma bupivacaine concentrations and simultaneous cytokine levels.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"605\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.082644628099173%\"\u003e\n \u003cp\u003e\u003cstrong\u003eTime\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.31404958677686%\"\u003e\n \u003cp\u003e\u003cstrong\u003eBupivacaine\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.892561983471076%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eCytokine levels\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.87603305785124%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eSpearman\u0026apos;s rho\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.75206611570248%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP Value\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.082644628099173%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.066006600660065%\" rowspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003e30 min\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.277227722772277%\" rowspan=\"3\"\u003e\n \u003cp\u003e1.519 \u0026plusmn; 0.919\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.881188118811881%\" valign=\"top\"\u003e\n \u003cp\u003eIL-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.122112211221122%\" valign=\"top\"\u003e\n \u003cp\u003e29,295 \u0026plusmn;\u0026nbsp;28,686\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.851485148514852%\" valign=\"top\"\u003e\n \u003cp\u003e0,111\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.735973597359736%\" valign=\"top\"\u003e\n \u003cp\u003e0,558\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.066006600660065%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.5609756097561%\" valign=\"top\"\u003e\n \u003cp\u003eIL-6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.21951219512195%\" valign=\"top\"\u003e\n \u003cp\u003e127,599 \u0026plusmn; 90,454\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.951219512195124%\" valign=\"top\"\u003e\n \u003cp\u003e0,182\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.390243902439025%\" valign=\"top\"\u003e\n \u003cp\u003e0,335\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.878048780487806%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.5609756097561%\" valign=\"top\"\u003e\n \u003cp\u003eTNF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.21951219512195%\" valign=\"top\"\u003e\n \u003cp\u003e86,411 \u0026plusmn; 69,592\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.951219512195124%\" valign=\"top\"\u003e\n \u003cp\u003e0,101\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.390243902439025%\" valign=\"top\"\u003e\n \u003cp\u003e0,595\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.878048780487806%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.066006600660065%\" rowspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003e2 hour\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.277227722772277%\" rowspan=\"3\"\u003e\n \u003cp\u003e1,664 \u0026plusmn; 0,787\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.881188118811881%\" valign=\"top\"\u003e\n \u003cp\u003eIL-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.122112211221122%\" valign=\"top\"\u003e\n \u003cp\u003e44,532\u0026plusmn; 42,613\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.851485148514852%\" valign=\"top\"\u003e\n \u003cp\u003e0,529\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.735973597359736%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,003*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.066006600660065%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.5609756097561%\" valign=\"top\"\u003e\n \u003cp\u003eIL-6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.21951219512195%\" valign=\"top\"\u003e\n \u003cp\u003e120,324 \u0026plusmn; 111,081\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.951219512195124%\" valign=\"top\"\u003e\n \u003cp\u003e0,577\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.390243902439025%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,001*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.878048780487806%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.5609756097561%\" valign=\"top\"\u003e\n \u003cp\u003eTNF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.21951219512195%\" valign=\"top\"\u003e\n \u003cp\u003e99,153 \u0026plusmn; 84,655\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.951219512195124%\" valign=\"top\"\u003e\n \u003cp\u003e0,274\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.390243902439025%\" valign=\"top\"\u003e\n \u003cp\u003e0,143\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.878048780487806%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.066006600660065%\" rowspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e6 hour\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.277227722772277%\" rowspan=\"3\"\u003e\n \u003cp\u003e1,335 \u0026plusmn; 0,508\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.881188118811881%\" valign=\"top\"\u003e\n \u003cp\u003eIL-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.122112211221122%\" valign=\"top\"\u003e\n \u003cp\u003e35,078 \u0026plusmn; 43,01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.851485148514852%\" valign=\"top\"\u003e\n \u003cp\u003e0,424\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.735973597359736%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,02*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.066006600660065%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.5609756097561%\" valign=\"top\"\u003e\n \u003cp\u003eIL-6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.21951219512195%\" valign=\"top\"\u003e\n \u003cp\u003e134,565 \u0026plusmn; 122,227\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.951219512195124%\" valign=\"top\"\u003e\n \u003cp\u003e0,463\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.390243902439025%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,011*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.878048780487806%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.5609756097561%\" valign=\"top\"\u003e\n \u003cp\u003eTNF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.21951219512195%\" valign=\"top\"\u003e\n \u003cp\u003e68,725 \u0026plusmn; 69,918\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.951219512195124%\" valign=\"top\"\u003e\n \u003cp\u003e0,342\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.390243902439025%\" valign=\"top\"\u003e\n \u003cp\u003e0,065\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.878048780487806%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.066006600660065%\" rowspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003e24 hour\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.277227722772277%\" rowspan=\"3\"\u003e\n \u003cp\u003e0,864 \u0026plusmn; 0,295\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.881188118811881%\" valign=\"top\"\u003e\n \u003cp\u003eIL-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.122112211221122%\" valign=\"top\"\u003e\n \u003cp\u003e37,869 \u0026plusmn; 45,628\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.851485148514852%\" valign=\"top\"\u003e\n \u003cp\u003e0,443\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.735973597359736%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,014*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.066006600660065%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.5609756097561%\" valign=\"top\"\u003e\n \u003cp\u003eIL-6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.21951219512195%\" valign=\"top\"\u003e\n \u003cp\u003e108,746 \u0026plusmn; 122,972\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.951219512195124%\" valign=\"top\"\u003e\n \u003cp\u003e0,41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.390243902439025%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,025*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.878048780487806%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.5609756097561%\" valign=\"top\"\u003e\n \u003cp\u003eTNF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.21951219512195%\" valign=\"top\"\u003e\n \u003cp\u003e70,159 \u0026plusmn; 79,274\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.951219512195124%\" valign=\"top\"\u003e\n \u003cp\u003e0,294\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.390243902439025%\" valign=\"top\"\u003e\n \u003cp\u003e0,114\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.878048780487806%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eValues are presented as mean \u0026plusmn; standard deviation. \u0026nbsp;*= p-value \u0026le; 0.05 is statistically significant\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Living liver donor, TAP block abdominal, Citokine, Bupivacaine","lastPublishedDoi":"10.21203/rs.3.rs-4322701/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4322701/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eTransversus abdominis plane (TAP) blocks were reported to reduce postoperative pain and opioid use. Local anesthetics modulate the local and systemic inflammatory reaction. Our aim was to examine the effect of TAP block with bupivacaine on the anti-inflammatory response in living liver donors (LLDs).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThe randomized prospective clinical study was carried out 72 LLDs, aged 18\u0026ndash;65 scheduled for right hepatectomy. TAP blocks were performed bilaterally with ultrasound guidance using 1.5 mg/kg of 0.5% bupivacaine for Group 2. Group 1 patients were control group. In both groups, blood samples were obtained preoperatively, 30 minutes and 2, 6, and 24 hours following injection for cytokine measurement. In Group 2, to examine the plasma bupivacaine level, blood samples were obtained preoperatively as well as 30 minutes and 1, 2, 6, 12, and 24 hours following injection. The primary outcome was to assess the effect of TAP block on the inflammatory response with cytokine levels.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eNo difference was observed between cytokine levels (Tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1) and interleukin 6 (IL-6) between Groups Significant positive correlations were observed between the plasma bupivacaine concentration and IL-1 and IL-6 levels at the 2nd, 6th and 24th hours\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eTAP block had no effect on the plasma cytokine concentration. Significant positive correlations were noted between the plasma bupivacaine concentration and IL-1 and IL-6 levels.\u003c/p\u003e","manuscriptTitle":"Anti-inflammatory Effect and Plasma Bupivacaine Concentrations After Transversus Abdominis Plane Block for Living Liver Donors: Prospective, Randomized, Blinded Clinical Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-11 18:22:55","doi":"10.21203/rs.3.rs-4322701/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c3eb9497-b887-4cd1-8741-1dc8ce08c326","owner":[],"postedDate":"June 11th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-07-05T01:36:05+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-11 18:22:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4322701","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4322701","identity":"rs-4322701","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}