{"paper_id":"a7a6a2e1-50fe-4097-988d-92679eccebdb","body_text":"ORIGINAL ARTICLE\nTranscervical intrauterine bupivacaine for the management\nof postoperative pain following endometrial balloon\nablation—a pre-trial toxicity study\nKalsang Bhatia & Oybek Rustimov & Manju Adhikary &\nSimon Hill\nReceived: 8 August 2008 / Accepted: 15 October 2008 / Published online: 4 November 2008\n# Springer-V erlag 2008\nAbstract The success of second-generation endometrial\nablation performed as day case or outpatient procedure is\noften hampered by severe postoperative pain. We adminis-\ntered dilute bupivacaine solution into the uterine cavity\nsoon after balloon ablation in ten consecutive women,\nlooking at the safety profile of bupivacaine. Three hours\npostoperative serum bupivacaine levels were well below the\ntoxic level in all women with no side effects reported.\nKeywords Transcervical . Bupivacaine .\nPostoperative pain relief . Balloon endometrial ablation\nIntroduction\nPostoperative analgesia is a key component of patient\nsatisfaction following day case or ambulatory surgery. The\nsuccess of second-generation endometrial ablation (EA)\ntechniques as a day case or office procedure may be\ncompromised by severe postoperative pain, which is known\nto occur from the release of prostaglandin from thermal\ndestruction of the endometrium causing severe uterine\ncramping [ 1]. Recent studies have also shown that the\nonset of postoperative pain is often delayed irrespective of\nthe type of anaesthesia, with onset typically about an hour\nafter the procedure, peaking at 2 –3 h often requiring opiates\nor antiemetics [ 2]. Although the need for postoperative pain\nrelief following second-generation ablation is recognised,\nthere are no published studies comparing different regimens\nfor this purpose. There is, therefore, a need to optimise\npostoperative pain management for this group of women\nwhich will in turn help improve acceptability and utilisation\nof these procedures in the outpatient and day case settings.\nIt is now a standard practice to prescribe either 100 mg\ndiclofenac and/or 1 g paracetamol suppositories up to 1 h prior\nto the procedure or soon after the procedure. Majority of the\ntime, when the procedure is performed under general\nanaesthesia, the postoperative pain management is at the\ndiscretion of the anaesthetist. It has been shown that up to\n25% of women require additional opiate analgesia [ 2], and\nthis figure is likely to be higher in endometrial balloon\nablation with longer treatment times. The need for opiates in\nturn increases the potential for delayed transfer from\nrecovery and discharge from hospital.\nLocal anaesthetic drugs act by causing a reversible\nconduction block along nerve fibres. They do not rely on\nthe systemic circulation for transport to the site of action,\nbut unwanted leak into the circulation is important in\nterminating their action and producing toxic side effects.\nThe rate of systemic absorption of local anaesthetics is\ndependent upon the total dose and concentration of drug\nadministered, route of administration, vascularity of the\nadministration site and the presence or absence of epinephrine\nin the anaesthetic solution. It is, therefore, generally recom-\nmended that these compounds should not be used in inflamed\nor traumatised tissues. Systemic absorption of local anaesthe-\ntic compounds may affect the cardiovascular and central\nnervous systems, which, although minimal at the serum\nconcentrations achieved with therapeutic doses, can be\nclinically significant with higher doses or greater systemic\nabsorption. Toxic blood concentrations occur mainly from\naccidental intravascular injection, delayed degradation\n(hepatic and renal) and overdosage. Effects initially include\nGynecol Surg (2009) 6:143 –146\nDOI 10.1007/s10397-008-0445-3\nK. Bhatia ( *) : O. Rustimov : M. Adhikary : S. Hill\nDepartment of Obstetrics and Gynaecology,\nRoyal Blackburn Hospital,\nHaslingden Road,\nBlackburn BB2 3HH, UK\ne-mail: Naviapo@aol.com\n\na feeling of inebriation and light-headedness followed by\nsedation, circumoral paraesthesia and twitching; convulsions\ncan occur in severe reactions. Cardiovascular effects include\ndepression of cardiac conduction and excitability, leading to\natrioventricular block, ventricular arrhythmias associated with\nperipheral vasodilatation, sometimes resulting in cardiac\narrest. Recent clinical reports and animal research suggest\nthat these cardiovascular changes are more likely to occur\nafter unintended intravascular injection of bupivacaine [3].\nBupivacaine is preferred for postoperative analgesia due\nto its longer duration of action compared to other local\nanalgesics. It takes up to 30 min for full effect with a half-\nlife of 2.7 h. The maximum therapeutic dose is 2 mg/kg\nwith a toxic plasma level of 4 mg/L. Dilute bupivacaine\nsolution administered intraperitoneally is commonly used\nfor postoperative pain relief after minimal access gynaeco-\nlogical and general surgery and their efficacy is evident in a\nnumber of randomised controlled trials [ 4–6]. Although no\nadverse effects have been reported, none of these studies\nmeasured serum bupivacaine levels or evaluated the side\neffect profile.\nIt is generally conceived that instillation of local\nanaesthetic solution into a uterine cavity treated with\nthermal ablation could accelerate its absorption with risk\nof toxicity, although there are no published studies to\nconfirm this and these risks remain theoretical. There are,\nhowever, a number of studies reporting on the safety and\nefficacy of topical local anaesthetic solutions (lignocaine\nand bupivacaine) when used in traumatised and inflamed\ntissue, for example, severe burns and spinal surgery with\nserum levels below the toxic range [ 7, 8]. This has\nprompted us to plan a randomised controlled trial to test\nthe postoperative analgesic efficacy of transuterine bupiva-\ncaine following second-generation endometrial ablation\nprocedures. Due to the lack of published evidence on the\nsafety of bupivacaine for this indication, we first conducted\na small pre-trial toxicity study, the results of which are\nreported in this paper.\nMaterials and methods\nThis is a prospective pilot study conducted in a district\ngeneral hospital in UK involving ten consecutive premen-\nopausal women undergoing endometrial balloon ablation\nfor dysfunctional uterine bleeding. All procedures were\nperformed under general anaesthesia as day case. All\nwomen had normal cervical smear and endometrial biopsy\nand did not have any desire for future pregnancy. Only\nthose women in whom the procedure was successfully\ncompleted were included. Women with cardiac disease,\nepilepsy or sensitivity to local anaesthetics were excluded\nfrom the study.\nEthical advice from the Local Research and Development\nCommittee (LREC) was obtained and formal ethical approval\nwas not needed for this study. V erbal and written information\nwith consent forms as advised by the LREC was used.\nThe objective of the study was to determine the safety and\nfeasibility of transcervical bupivacaine when instilled into the\nuterine cavity immediately after balloon ablation for the\nmanagement of postoperative pain. Main outcome measures\nwere serum bupivacaine levels (3 h postoperative) and the\nincidence of symptoms indicating clinical toxicity in the group.\nAll participants received postoperative analgesia as\nstandard practice (intravenous or rectal diclofenac and/or\nparacetamol postoperatively) for the unit. The participants\nalso received 50 mL of 0.25% bupivacaine (125 mg, not\nexceeding 2 mg/kg) which was instilled transcervically into\nthe uterine cavity on completion of the procedure.\nConsecutive women undergoing balloon ablation were\noffered the option of the new intervention in addition to\nstandard treatment for postoperative pain relief. Written and\ninformed consent was obtained. Demographic data including\nage, body mass index (BMI) and parity were collected. All\nprocedures were performed under general anaesthetic, and\nballoon ablation was performed using Thermachoice® III\n(Gynecare, Ethicon, Somerville, NJ, USA). After the comple-\ntion of the procedure, an appropriate-sized Foley catheter\n(depending on the dilatation of external cervical os) was\ninserted into the uterine cavity with 5 mL of water in the\ncatheter balloon. Sufficient traction was placed upon the inflated\nballoon to occlude the internal os, and in Trendelenberg ’s\nposition, 50 mL of 0.25% bupivacaine solution was injected\nthrough the catheter taking care to minimise any leakage. The\ntime of bupivacaine administration was noted and a spigot was\ninserted into the catheter to allow retention of bupivacaine\nwithin the endometrial cavity for at least 15–20 min.\nWhilst in the recovery room, usual monitoring for blood\npressure and pulse rate was performed. Pain scores were\nrecorded on a verbal scale of 0 to 4, which is the standard\npractice for scoring postoperative pain in the recovery room\nfor the East Lancashire Hospitals NHS trust (0 —none, 1 —\nmild pain, 2 —mild but moderate on movement, 3 —\nmoderate but severe on movement and 4 —severe at rest).\nThe catheter was removed approximately 15 –20 min after\nthe procedure before transfer to ward. Once on the ward, the\nco-investigator reviewed the participants enquiring into\nsymptoms such as pain, palpitation, circumoral paraesthesia\nand twitching. A serum sample for bupivacaine levels was\nobtained 3 h after administration and any additional\nanalgesia requirements were noted. Pain score at discharge\nwas also recorded. All women were given analgesia to take\nhome as usual (paracetamol and diclofenac).\nAnalysis of the serum samples were undertaken at the\nMedical Toxicology Laboratory, Guy ’s and St. Thomas ’\nHospital in London.\n144 Gynecol Surg (2009) 6:143 –146\n\nResults\nTen women received bupivacaine for postoperative pain\nrelief following Thermachoice® balloon ablation. The mean\nage was 43 years (range 33 –49 years) and the mean BMI\nwas 31.5 kg/m 2 (range 21 –43 kg/m 2); all were parous. One\nblood sample was sent in the wrong bottle and, hence, only\nnine samples were analysed by the laboratory. None of the\nwomen reported symptoms indicative of bupivacaine\ntoxicity. Serum bupivacaine levels (3 h postoperative)\nranged between <0.1 and 1.3 mg/L, being well below the\ntoxic level (4 mg/L) in all women. Levels were negligible\n(<0.1 mg/L) in four women (see Table 1).\nTable 1 also shows the pain scores and postoperative\nanalgesia received by the participants. None of the women\nreceived analgesia preoperatively: nine out of ten women\nreceived diclofenacand paracetamol soon after the procedure\nas part of standard practice for the anaesthetist concerned.\nTwo out of ten women (both had uterine curettage to thin the\nendometrium prior to EA) also needed parenteral morphine.\nBoth these women stayed for overnight observation since the\nprocedures were performed in the late afternoons. The mean\npain score for the group (scale of 0 –4) was 1.1 (range 0 –3)\nin the recovery room and 0.7 (range 0 –1) at discharge.\nDiscussion\nThis pilot study shows that, in the dosages used, intrauterine\nbupivacaine given soon after endometrial balloon ablation\nappears to be safe and free of any clinical toxicity, although\nthis needs to be confirmed in a larger study.\nA dilute solution of bupivacaine (0.25%) was specifi-\ncally used in this study to reduce the possibility of systemic\nabsorption of bupivacaine from the heated endometrial\nsurface. Toxic serum levels are associated mainly with\naccidental intravascular injection or overdosage; the risk of\nsystemic absorption is likely to be minimal with topical\nadministration of therapeutic doses. However, by occluding\nthe cervical os by a Foley catheter as in this study, there is a\npotential for increased toxicity due to uncontrolled rise in\nintrauterine pressure (IUP) and, hence, caution needs to be\nexercised especially when giving larger doses. Hasham\net al. conducted a small randomised controlled trial\ncomparing IUP and fluid deficit in two groups of women\nundergoing endometrial laser ablation (ELA) with and\nwithout control of intrauterine pressures. They demonstrated\nthat control of IUP during ELA was effective in preventing\nabsorption of irrigating fluid [ 9].\nIntraperitoneal bupivacaine has been used in dosages\nbetween 50 and 285 mg for postoperative pain following\nlaparoscopic procedures in general surgical and gynaeco-\nlogical practice and dosages of less than 100 mg were not\nfound to be effective [ 7, 8]. In this study, although a Foley\ncatheter was used to occlude the cervical os, there is potential\nfor leakage and, therefore, for the intervention to be\neffective, 125 mg of bupivacaine was used without titrating\nfor body weight, making sure the maximum therapeutic dose\n(2 mg/kg) was not crossed in smaller women.\nThe half-life of bupivacaine is 2.7 h and, hence, serum levels\nwere taken at 3 h postoperativel y. Serum bupivacaine after\n3 h was well below the toxic level in all women—even double\nthe measured levels were still we ll within the accepted safety\nlimit. No side effects attributable to bupivacaine toxicity were\nreported in this small series, consistent with the serum levels.\nIt is difficult to ascertain whether the intervention was\neffective in relieving postoperative pain since almost all\nparticipants also received both diclofenac and paracetamol\nTable 1 Serum bupivacaine levels, pain score and postoperative analgesia in study participants\nParticipant number\n(study group)\nSerum bupivacaine\n(3 h postoperative; mg/L)\nPain scores at recovery/\ndischargea\nDiclofenac Paracetamol Other\nanalgesia\nMorphine\n(total dose)\n1 <0.1 0/1 100 mg PR 1 g PR Codeine 60 mg –\n2b 0.1 3/0 100 mg PR 1 g iv Codeine 60 mg 10 mg\n3 Wrong sample 0/0 100 mg PR 1 g PR ––\n4b 0.5 2/0 50 mg iv 1 g Buscopan 10 mg 10 mg\n5 <0.1 1/1 –– Codeine 60 mg –\n6 0.1 1/1 75 mg iv 1 g PR ––\n7 1.3 1/1 50 mg iv 1 g iv ––\n8 <0.1 2/1 100 mg PR 1 g PR Codeine 60 mg –\n1gi v\n9 <0.1 0/1 75 mg iv 1 g PR Co-codamol×2 –\n10 0.5 1/1 75 mg iv 1 g PR Codeine phos 60 mg –\na Pain score—verbal scale of 0 –4 (standard use in recovery —East Lancashire Hospital NHS Trust; 0 —none, 1—mild pain, 2 —mild but moderate\non movement, 3 —moderate but severe on movement and 4 —severe at rest)\nb Required overnight stay\nGynecol Surg (2009) 6:143 –146 145\n\ngiven immediate postoperatively as a prophylactic standard\npractice. Moreover, the study was not designed to assess\nthis outcome measure. Two out of ten women in this study\nrequired parenteral opiates: a recent unpublished local audit\nreported an opiate requirement of 70% in women undergo-\ning endometrial balloon ablation, reflecting the need to\noptimise postoperative care in this group of women.\nFor the intervention to be effective, it is important to\nreduce leakage from the cervix by obtaining a good seal,\nmaintain Trendelenberg ’s position and slow injection into\nthe catheter whilst allowing the uterus to relax when\nresistance is encountered from uterine contractility. The use\nof smaller volume of more concentrated bupivacaine\nsolution may be another option. Bupivacaine with adrenaline\nhelps slow systemic absorption to allow more sustained local\nanaesthetic effect and reduce toxicity and, hence, may be\nmore appropriate for this purpose.\nConclusion\nIntrauterine instillation of dilute bupivacaine solution (125 mg)\nsoon after endometrial balloon ablation appears to be safe\nand feasible, although we appreciate that measurement of\nIUP whilst the Foley catheter was in situ would have\nprovided additional valuable information. Our proposed\nrandomised controlled trial could demonstrate a useful\nmethod of providing postoperative analgesia for endometrial\nablation procedures.\nAcknowledgement We would like to thank the Biochemistry\nDepartment at Royal Blackburn Hospital for supporting the study\nand arranging transportation of the blood samples and the Medical\nToxicology Laboratory, Guy ’s and St. Thomas ’ Hospital in London\nfor analysing the samples. 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