Although epidural analgesia (EDA) is considered standard postoperative analgesia for open gastrectomy, it has been unclear whether EDA has benefits in laparoscopic gastrectomy (LG) because postoperative pain after a laparoscopic procedure is significantly reduced. We are conducting a two-arm, single-center, prospective randomized non-inferiority trial to evaluate the postoperative pain relief of patient-controlled intravenous analgesia (PCIA) compared to EDA. A total of 132 patients undergoing LG will be randomized to EDA and PCIA groups (n=64 each) for postoperative pain control. The primary endpoint is postoperative pain at 24 h after surgery. This study will clarify the optimal pain management after LG

Fujiwara, Toshiyoshi

Kagawa, Shunsuke

Kikuchi, Satoru

Kuroda, Shinji

Kuwada, Kazuya

Matsusaki, Takashi

Mitsuhashi, Toshiharu

Morimatsu, Hiroshi

Nishizaki, Masahiko

Okayama University Scientific Achievement Repository

E nhanced recovery after surgery (ERAS) protocols are composed of multimodal perioperative care,  and they have proven valuable in reducing complica-tions,  shortening the postoperative length of hospital stays,  and costs [1 , 2].  Epidural analgesia (EDA) is considered an indispensable procedure after open abdominal surgery in ERAS protocols since EDA has been shown to provide superior pain relief and decreased the rate of postoperative complications after abdominal surgery [3 , 4].In recent years,  laparoscopic gastrectomy for gastric cancer has become a standard procedure.  It has been reported that the laparoscopic approach is associated with a reduction in postoperative pain and opioid con-sumption,  lower morbidity,  faster recovery and shorter postoperative length of hospital stays compared to open surgery [5-8].  Although EDA is an excellent pain relief modality,  the role of EDA in laparoscopic surgery is unclear.  Several clinical studies showed that the use of EDA slowed down the recovery after laparoscopic col-orectal surgery [9-11].  Moreover,  the use of EDA requires an invasive and specialized technique for cath-eter placement and has the potential to cause severe complications such as epidural hematoma or abscess [12].  It was also reported that one-third of EDA might not function adequately because of catheter misplace-ment or deviation or an inadequate dose [13].In postoperative pain control,  multimodal analgesia has been recommended because it provides excellent pain relief with minimized adverse events related to analgesia [14].  Patient-controlled intravenous analgesia (PCIA) plays an important role in multimodal analgesia concepts,  and is a safe,  less-invasive and effective anal-Acta Med.  Okayama,  2018Vol.  72,  No.  1,  pp.  95-98CopyrightⒸ 2018 by Okayama University Medical School.http ://escholarship.lib.okayama-u.ac.jp/amo/Clinical Study ProtocolRandomized Controlled Trial of Epidural versus Patient-controlled Intravenous Analgesia for Postoperative Pain Control after  Laparoscopic GastrectomySatoru Kikuchia＊,  Shinji Kurodaa,  Masahiko Nishizakia,  Takashi Matsusakib,  Toshiharu Mitsuhashic,  Kazuya Kuwadaa,  Shunsuke Kagawaa,  Hiroshi Morimatsub,  and Toshiyoshi FujiwaraaDepartments of aGastroenterological Surgery,  bAnesthesiology and Resuscitology,  Okayama University Graduate School of Medicine,  Dentistry and Pharmaceutical Sciences,  cCenter for Innovative Clinical Medicine,  Okayama University Hospital,   Okayama 700-8558,  Japan Although epidural analgesia (EDA) is considered standard postoperative analgesia for open gastrectomy,  it has been unclear whether EDA has benefits in laparoscopic gastrectomy (LG) because postoperative pain after a laparoscopic procedure is significantly reduced.  We are conducting a two-arm,  single-center,  prospective ran-domized non-inferiority trial to evaluate the postoperative pain relief of patient-controlled intravenous analge-sia (PCIA) compared to EDA.  A total of 132 patients undergoing LG will be randomized to EDA and PCIA groups (n = 64 each) for postoperative pain control.  The primary endpoint is postoperative pain at 24 h after surgery.  This study will clarify the optimal pain management after LG.Key words:  laparoscopic gastrectomy,  epidural analgesia,  patient-controlled intravenous analgesia,  pain reliefReceived August 7, 2017 ; accepted October 12, 2017.＊Corresponding author. Phone : +81-86-235-7255; Fax : +81-86-221-8775E-mail : satorukc@okayama-u.ac.jp (S. Kikuchi)Conflict of Interest Disclosures: No potential conflict of interest relevant to this article was reported.gesia using a peripheral vein.We are conducting a prospective,  randomized con-trolled trial to evaluate the pain relief efficacy of PCIA compared to that of EDA after laparoscopic gastrec-tomy (LG).MethodsStudy design. This is a two-arm,  single-center,  prospective randomized non-inferiority trial to evaluate the postoperative pain relief provided by PCIA com-pared to that of EDA following laparoscopic gastrec-tomy.  This trial is being conducted at the Okayama University Hospital.  A total of 132 eligible patients undergoing laparoscopic gastrectomy have been ran-domized to the EDA and PCIA groups (n = 64 each) for postoperative pain control (Fig. 1).Ethical ConsiderationThis study is being conducted in compliance with the principles of the Declaration of Helsinki,  and this pro-tocol has been approved by the Institutional Review Board of the Okayama University Hospital (No. 1705-004).  This trial is registered with the University Hospital Medical Information Network Clinical Trial Registry (UMIN000027643).EndpointsThe primary endpoint is postoperative pain at rest 24 h after surgery,  which is assessed using a numerical rating scale (NRS) [15].  The patients’ NRS pain scores are graded from 0 (no pain) to 10 (imaginable worst pain),  and self-reported by the patients and recorded by the nursing staff.  Secondary endpoints include the achievement day of discharge criteria,  the length of the postoperative hospital stay,  postoperative complica-tions,  postoperative pain on days 2 , 3 , 4 after surgery,  additional doses of analgesics,  adverse events related to analgesia,  and the patient’s satisfaction.  The achieve-ment day of discharge criteria is used to assess the recovery after surgery; this is considered a more spe-cific outcome parameter than the length of postopera-tive hospital stays because social and logistic factors are not interfering.  The criteria are defined as eating a normal diet,  no complaints of pain,  full mobilization comparable to that of the patient’s preoperative status,  and no complications for 24 h.  All patients will be fol-lowed-up until a regular checkup at approx.  1 month after surgery.Postoperative complications are graded using the Clavien-Dindo classification system [16].  The postop-erative pain is assessed using a NRS at rest and move-ment,  and routine evaluation twice daily starts the evening of the surgery day and is continued until post-operative day (POD) 4.  The adverse events related to analgesia include sedation,  postoperative nausea and vomiting,  hypotension,  and urinary retention.  The patient’s satisfaction is assessed using a 5-point Likert scale from very dissatisfied (1) to very satisfied (5).  Safety related to the interventions is also being evalu-ated.Eligibility CriteriaAll of the patients who meet the eligibility criteria based on the inclusion and exclusion criteria,  which are listed in Table 1,  are being enrolled in this study from July 2017 to June 2019.96 Kikuchi et al. Acta Med.  Okayama　Vol.  72,  No.  1Patients for laparoscopic gastrectomyPre-operative assessment of eligibilityObtainment of written informed consentRandomizationEDA PCIASurgical procedureFollow-up and AnalysisFig. 1　 Trial ﬂowchart.  EDA,  epidural analgesia; PCIA,  patient- controlled intravenous analgesia.RandomizationAfter the patients’ fulfillment of the eligibility criteria was confirmed,  the patients receive verbal and written information about the study,  and their written consent is obtained.  After registration in the Data Center,  each patient is randomly assigned to the EDA or PCIA group with the use of a computer-generated list.  Allocation is performed by a stratified permuted block method.  For medical and logistic reasons,  blinding is not performed because it is not realistic for this study.  The stratified factors are age,  sex,  American Society of Anesthesiolo-gists (ASA) Physical Status classification,  and surgical procedure.Treatment MethodsIntervention. In all patients,  the clinical path after LG in our institution will be used in order to stan-dardize the perioperative treatment in two groups.  In the EDA group,  an epidural catheter is inserted at the thoracic level (Th8-10) before the induction of anesthe-sia using loss of resistance.  The epidural space is con-firmed by performing an absorption test and a 3-ml bolus of 1% lidocaine with epinephrine (dilution 1 : 100,000).  A 5-ml bolus of 0.2% ropivacaine is started as soon as the epidural catheter is inserted,  and a con-tinuous infusion or bolus injection of 0.2% ropivacaine with fentanyl (1 µg/ml) is performed until the end of surgery depending on the anesthesiologist’s decision based on the patient’s vital signs.In both the EDA and PCIA groups,  the induction of general anesthesia is performed with propofol (target controlled infusion [TCI] 2-4 µg/ml),  remifentanil (0.2-0.5 µg/kg/min),  and rocuronium bromide (0.5-0.6 mg/kg) for muscle paralysis.  Anesthesia is main-tained with the total intravenous venous anesthesia (TIVA) technique using a propofol TCI and remifent-anil infusion.  Rocuronium bromide is used for muscle relaxation as needed.  All cases will be extubated in the operating room if possible.Postoperatively,  EDA is maintained at a rate of 2 to 6 ml/h (target: NRS < 4) using an epidural patient-con-trolled analgesia (PCA) pump.  A bolus of 3 ml is allowed every 15 min.  In the PCIA group,  intravenous fentanyl (10 µg/ml) is administered at 0-1 ml/h at the end of the surgery.  A bolus of 1 ml is allowed every 15  min up to the maximal dose of 40 µg/h (target: NRS<4).Both interventions are planned to be discontinued on POD 2,  but both can be continued until POD 7 if the analgesia team judges that a prolonged application is beneficial for the patient.  All patients received celecoxib (200 mg × 2/day,  oral) from POD 3 as baseline analge-sia unless contraindicated.  The pain score is assessed twice daily at rest and on mobilization or coughing by nursing staff.  Additional analgesics including loxopro-fen sodium hydrate (60 mg,  oral),  pentazocine (15 mg,  intravenous),  flurbiprofen axetil (50 mg,  intravenous),  and acetaminophen (1,000 mg,  intravenous) are admin-istered when the patient complains of pain (NRS > 3).Adverse events. The adverse events related to PCIA and to EDA including sedation,  postoperative nausea and vomiting,  hypotension,  and urinary reten-tion are monitored during the patient’s hospital stay.  Moreover,  severe complications such as epidural hema-toma or abscess related to EDA are also monitored.Statistical ConsiderationSample size. Based on retrospective data from our institution regarding laparoscopic gastrectomy for gastric cancer,  the NRS scores (mean ± standard devia-tion) at rest 24 h after surgery were 2.11 ± 1.9 and 2.36 ± 1.8 in the EDA group and the PCIA group,  respectively.  In this study,  a similar population is included (according to the eligibility criteria) compared February 2018 Epidural vs. PCIA after LG 97Table 1　 Patient inclusion and exclusion criteriaInclusion criteria　(1)  Patients who are scheduled to undergo LG including TG,  DG,  and PG　(2) Aged 20-80 years　(3) Patients who can provide written informed consentExclusion criteria　(1) ASA-PS≥4　(2) Patients undergoing anticoagulant therapy　(3) Medical contraindication for EDA　(4) Abnormal anatomy of the spinal column　(5) Neoadjuvant chemotherapy　(6) Immunodeﬁciency　(7) Palliative surgery　(8) Emergency surgery　(9)  Otherwise judged by the investigator as unsuitable for enroll-mentASA-PS,  American Society of Anesthesiologists-Physical Status;  DG,  distal gastrectomy; EDA,  epidural analgesia; LG,  laparoscopic gastrectomy; PG,  proximal gastrectomy; TG,  total gastrectomy.to the retrospective data.  Therefore,  the standard devi-ation of NRS scores in this study is estimated to be smaller than that of the retrospective data.  We antici-pate a 10% lower standard deviation compared to the retrospective data,  and ensuring that at least 80% power with a one-sided alpha of 5% and a non-inferior-ity margin of 1 in terms of NRS score,  62 patients per each group are needed.  To compensate for potential exclusions or withdrawals,  we will include a total of 132 patients.Statistical analysis. Student’s T-test is used to analyze continuous variables.  P-values < 0.05 are con-sidered significant.  The statistical analyses will be per-formed by using JMP 11.2 (SAS Institute,  Cary,  NC,  USA).Acknowledgments.　The authors thank Professor Shiro Hinotsu at the Center for Innovative Clinical Medicine,  Okayama University Hospital for his considerable assistance in writing this protocol.References 1. Varadhan KK,  Neal KR,  Dejong CH,  Fearon KC,  Ljungqvist O and Lobo DN: The enhanced recovery after surgery (ERAS) path-way for patients undergoing major elective open colorectal surgery:  a meta-analysis of randomized controlled trials.  Clin Nutr (2010) 29: 434-440. 2. Roulin D,  Donadini A,  Gander S,  Griesser AC,  Blanc C,  Hübner M,  Schäfer M and Demartines N: Cost-eﬀectiveness of the implemen-tation of an enhanced recovery protocol for colorectal surgery.  Br J Surg (2013) 100: 1108-1114. 3. Pöpping DM,  Elia N,  Marret E,  Remy C and Tramèr MR: Protective eﬀects of epidural analgesia on pulmonary complications after abdominal and thoracic surgery: a meta-analysis.  Arch Surg (2008) 143: 990-999. 4. Block BM,  Liu SS,  Rowlingson AJ,  Cowan AR,  Cowan JA Jr and Wu CL: Eﬃcacy of postoperative epidural analgesia: a meta-anal-ysis.  JAMA (2003) 290: 2455-2463. 5. 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McLeod G,  Davies H,  Munnoch N,  Bannister J and MacRae W:  Postoperative pain relief using thoracic epidural analgesia: out-standing success and disappointing failures.  Anaesthesia (2001) 56: 75-81.14. Kehlet H and Wilmore DW: Evidence-based surgical care and the evolution of fast-track surgery.  Ann Surg (2008) 248: 189-198.15. Hjermstad MJ,  Fayers PM,  Haugen DF,  Caraceni A,  Hanks GW,  Loge JH,  Fainsinger R,  Aass N and Kaasa S; European Palliative Care Research Collaborative (EPCRC): Studies comparing Numerical Rating Scales,  Verbal Rating Scales,  and Visual Analogue Scales for assessment of pain intensity in adults: a systematic literature review.  J Pain Symptom Manage (2011) 41: 1073-1093.16. Dindo D,  Demartines N and Clavien PA: Classiﬁcation of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of survey.  Ann Surg (2004) 240: 205-213.98 Kikuchi et al. Acta Med.  Okayama　Vol.  72,  No.  1

Randomized Controlled Trial of Epidural versus Patient-controlled Intravenous Analgesia for Postoperative Pain Control after Laparoscopic Gastrectomy

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Randomized Controlled Trial of Epidural versus Patient-controlled Intravenous Analgesia for Postoperative Pain Control after Laparoscopic Gastrectomy

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