PAIN. Editor s key points. A. Perniola 1 *,F.Fant 1, A. Magnuson 2, K. Axelsson 1 and A. Gupta 1

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1 British Journal of Anaesthesia 112 (2): (214) Advance Access publication 31 October 213. doi:1.193/bja/aet345 PAIN Postoperative pain after abdominal hysterectomy: a randomized, double-blind, controlled trial comparing continuous infusion vs patient-controlled intraperitoneal injection of local anaesthetic A. Perniola 1 *,F.Fant 1, A. Magnuson 2, K. Axelsson 1 and A. Gupta 1 1 Department of Anesthesiology and Intensive Care and 2 Clinical Epidemiology and Biostatistical Unit, Clinical Reaserch Centre, Örebro University Hospital, School of Health and Medical Sciences, Örebro University, SE Örebro, Sweden * Corresponding author. perniola.d@gmail.com Editor s key points Effective analgesic techniques that reduce opioid consumption may improve postoperative recovery. There is evidence that intraperitoneal (i.p.) local anaesthetics can be effective. This study compared continuous with intermittent patient-controlled i.p. levobupivacaine (PCipA) for postoperative analgesia. PCipA resulted in similar pain control, reduced opioid consumption and improved gastrointestinal function. Further work is needed to evaluate this potentially beneficial analgesic technique. Background. Local anaesthetics (LA) injected intraperitoneally have been found to decrease postoperative pain. This double-blind randomized study was performed comparing continuous infusion or patient-controlled intraperitoneal (i.p.) bolus injection of LA. The primary endpoint was supplemental opioid consumption during the first 24 postoperative hours. Methods. Two multi-hole catheters were placed intraperitoneally at the end of the surgery in 4 patients undergoing elective abdominal hysterectomy. The patients were randomized into two groups: : patients self-injected 1 ml of levobupivacaine 1.25 mg ml 21 via the i.p. catheter as needed, maximum once per hour, and had continuous saline infusion 1 ml h 21 into the second catheter. : patients received a continuous infusion of 1 ml h 21 of levobupivacaine 1.25 mg ml 21 intraperitoneally through one catheter and 1 ml saline as bolus as needed via the other. Ketobemidone was administered intravenously as rescue medication. Results. Total ketobemidone consumption during 24 h was lower in compared with (mean 23.1 vs 35.7 mg, P¼.4). No differences in the median pain scores were found between the groups. Earlier return of gastrointestinal (GI) function was found in vs (mean 1.5 vs 2.2 days, P,.1), which also resulted in earlier home-readiness (mean 1.9 vs 2.7 days, P¼.4). Conclusions. A statisticallysignificant opioid-sparing effectwas found when patient-controlled levobupivacaine was administered intraperitoneally as needed compared with continuous infusion. This was associated with a faster return of GI function and home-readiness. There was, however, a wide confidence interval in the primary endpoint, opioid consumption. Keywords: abdominal hysterectomy; local anaesthetics; postoperative pain Accepted for publication: 11 August 213 It is estimated that one woman in 1 undergoes hysterectomy in Sweden. 1 Abdominal hysterectomy is associated with moderate-to-severe postoperative pain. 2 Traditional methods for postoperative pain management include opioids administered systemically using patient-controlled i.v. analgesia (PCA), or neuroaxially via epidural or spinal injections. However, pain relief, specifically on movement, is not always adequately controlled when using PCA, despite moderate large doses of morphine. This is associated with side-effects such as postoperative nausea and vomiting (PONV), tiredness, pruritus, headache, and constipation. 3 Therefore, epidural or intrathecal analgesia may be considered by some to be the gold standard for pain management after abdominal surgery, and leads to enhanced and prolonged postoperative analgesia. 4 Although concerns remain regarding complications after central blocks, specifically in older patients, 5 recent evidence suggests that these are extremely rare. 6 There has been recent interest in alternative methods for analgesia with minimal side-effects and a trend towards movement from central blocks towards other peripheral and less invasive methods for pain relief. 7 One such technique is wound infiltration, intraperitoneal (i.p.) administration of & The Author [213]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please journals.permissions@oup.com

2 Intraperitoneal local anaesthetics for pain relief after abdominal hysterectomy BJA local anaesthetics (LA), or both Continuous i.p. infusion of LA has been reported to result in a 3 4% morphine-sparing effect and a reduction in postoperative nausea. 12 Several studies have shown that patient-controlled bolus administration of LA during neuraxial or peripheral nerve block gives better postoperative analgesia compared with continuous infusions Therefore, we decided to test the hypothesis that patient-controlled i.p. analgesia (PCipA) with LA would reduce pain intensity and thereby supplemental opioid consumption compared with continuous infusion of LA. The primary aim was therefore to analyse rescue analgesic consumption during 24 h after operation after abdominal hysterectomy in patients receiving continuous LA infusion compared with intermittent patient-controlled i.p. injections. The secondary outcomes were analgesic consumption during 4 h, pain intensity, incidence of nausea and vomiting, maximum expiratory pressure, time to mobilization, and length of hospital stay, and also health-related quality of life at 1 and 3 months. Methods This study was registered in an international registry, clinicaltrials.gov (identification number NCT149275) before patient recruitment. The study was performed at the Department of Anaesthesiology and Intensive Care and the Department of Gynaecological Surgery, University Hospital, Örebro, Sweden, and monitored by an external organization not involved in any way with the study. This unit is a quality-based organization located within the hospital and initiates and monitors clinical trials. After approval from the Regional Ethics Committee, Uppsala, oral and written informed consent was obtained from 4 patients (ASA status I II), aged 4 65 yr undergoing elective abdominal hysterectomy with or without salpingo-oophorectomy in this randomized, double-blind study. The exclusion criteria were: patients undergoing surgery for suspected gynaecological cancer, patients on chronic analgesic medication, those with known allergy to LA, patients participating in another clinical study, and those who had difficulty in understanding Swedish. Randomization and blinding On the day of surgery, the Hospital Pharmacy randomized patients into two groups (2 in each group) using computergenerated randomized numbers inserted into sealed opaque envelopes and marked 1 4. All personnel involved in patient management were fully blinded to the method of analgesia until the study was completed. Anaesthesia and surgery All patients were premedicated with midazolam.1 mg kg 21 orally and paracetamol 1 g was given orally every 6 h with the first dose at the time of premedication. Anaesthesia was induced with fentanyl 1 2 mg kg 21 and propofol 1 2 mg kg 21 intravenously. Tracheal intubation was performed after muscle relaxation with rocuronium.5 mg kg 21 and anaesthesia was subsequently maintained with sevoflurane 1 3% and oxygen 33% in air. End-tidal CO 2 was maintained between 4.5 and 5.5 kpa using mechanical ventilation in a low-flow breathing system with CO 2 absorber. Monitoring included non-invasive arterial pressure, heart rate, peripheral oxygen saturation, end-tidal gas monitoring, ECG, and muscle relaxation using the train-of-four stimulation. Sevoflurane concentration was adjusted in order to maintain adequate anaesthetic depth, assessed clinically, and fentanyl was given intermittently intravenously when required for analgesia during the operation. Muscle relaxation was reversed at the end of surgery using glycopyrrolate (.5 mg) and neostigmine (2.5 mg). Hysterectomy was performed using either a lower-abdominal midline incision or a Pfannenstiel incision, depending on the choice of the operator taking into consideration the size of the uterus and expected surgical difficulty. Catheter insertion and postoperative pain management Before closing the peritoneum, two multi-hole catheters were inserted percutaneously by the surgeon; one catheter was tunnelled from the left side and the other from the right side, about 1 2 cm lateral to the abdominal incision and the tip of the catheters was placed supravaginally as described previously. 2 The catheters were not fixed intraperitoneally. In all patients, levobupivacaine 1.25 mg ml 21 (2 ml) was injected subcutaneously along both sides of the incision before skin closure by the surgeon; an additional 2 ml was injected via one of the catheters into the peritoneal cavity. The pharmacysent (i) one blinded bag, containing 5 ml of levobupivacaine 1.25 mg ml 21 or placebo (normal saline) and (ii) one elastomeric pump (On-Q Pain BusterR, ref PS12571; I-Flow Corp., Lake Forest, CA, USA) containing 5 ml of levobupivacaine 1.25 mg ml 21 or placebo (normal saline). Whenthe patient arrivedinthe post-anaesthesia care unit (PACU), the infusions were set up, connected, and started by one of the co-authors immediately as described below. The time of start of infusion was considered t¼. : PCipAwith LA. The patients self-administered 1 ml of levobupivacaine via the first i.p catheter as required (maximum once per hour) during the first 48 h after the operation via an electronic pump (Abbot GemStar, Abbot Laboratories, North Chicago, IL, USA) over 1 min. Normal saline was infused at 1 ml h 21 via the second i.p catheter using the elastomeric pump. : continuous i.p. infusion of LA. Patients received a continuous infusion of levobupivacaine 1 ml h 21 intraperitoneally through the first catheter via the elastomeric pump and saline as bolus injection via the second i.p. catheter using the electronic pump. After 48 h, the i.p. bolus/infusion was stopped and both catheters were removed. Rescue medication and postoperative ward All patients received 2 4 mg ketobemidone intravenously, an opioid analgesic equipotent with morphine, 18 intermittently by the staff nurse if pain was.3 on the numerical rating scale (NRS) (, no pain; 1, worst imaginable pain). Analgesics were administered on patient request, irrespective of whether 329

3 BJA Perniola et al. the pain was.3 at rest, on sitting, or during coughing. The patients were observed in the PACU until the day after the surgery. In the case of severe postoperative nausea or vomiting (PONV) not relieved by anti-emetics, the nursing staff were allowed to administer non-steroidal anti-inflammatory drugs (NSAIDs) for pain management in order to reduce opioid-induced PONV. Recording and measurements In addition to the routine postoperative protocols, the following parameters were recorded: Pain and analgesia: pain at the site of the incision, deep (visceral) pain, and pain on coughing at 1, 4, 12, 24, and 48 h were measured using NRS. Rescue analgesic (ketobemidone) consumption was measured during 4, 24, and h. Side-effects: nausea, vomiting, or both ( 4, 4 24, and h) were recorded on a yes/no score; anti-emetic consumption during 24 and h was also recorded. Sedation (before operation, at 4, 24, and 48 h) was recorded by nurses using a 1 scale (, awake; 1, verbally arousable). Expiratory muscle function: this was measured before and 24 and 48 h after the operation using maximum expiratory pressure (P Emax ) (MicroMedical, Moreton-in-Marsh, UK), in a similar way as described in previous studies P Emax was measured twice by asking the patient to blow rapidly using the full abdominal force after a maximal inspiration while in the semi-reclining position. The best of two measurements was recorded. Recovery parameters: the ability to walk with and without support, time to start drinking, eating, and time to return of gastrointestinal (GI) function (bowel movement or passing flatus), postoperative home-readiness, and length of hospital stay were recorded once a day by nurses in the gynaecological ward. Standardized home-readiness criteria were used that have been described previously. 212 LA toxicity: the nurses were informed about the common signs and symptoms of LA toxicity and the patients told to inform the nurses of any side-effects and symptoms. Health-related quality of life: this was measured using the written form of SF-36 questionnaire before and 1 and 3 months after the operation in both groups and the patients were asked to return it by post. The SF-36 is a validated health survey consisting of 36 questions that measure eight health concepts and has been translated and validated into the Swedish language. 212 A higher score indicates an improved level of function. Statistics In a previous study, 2 the mean [standard deviation (SD)] total morphine consumption during 24 h was found to be 3 mg (SD 17) in patients receiving continuous i.p. LA. Our hypothesis was that this could be reduced by 5% to a mean value of 15 mg (SD 8) in patients receiving PCipA with LA. The sample size was calculated using the unpaired twosided t-test. Assuming b¼.2 (power 8%) and a¼.5, we determined that we would require 28 patients (14 per group) in order to achieve statistical significance for the primary endpoint. We recruited 4 patients in order to achieve adequate power in the case of missing data or patient drop out. The mean and SD are used to summarize continuous variables, while categorical variables are presented as numbers (%). Unpaired t-test with 95% confidence intervals (CIs) and P-values was used to analyse differences between study groups for morphine consumption and other continuous variables distributed approximately normally with or without log transformation. The Shapiro Wilk test was used to evaluate normal distribution and if non-normality was found, logtransformation was performed before statistical evaluation. The results were then transformed back to original scale and the effect parameter is therefore the ratio of geometric means. The results are presented as the mean ratios together with 95% CI. Owing to multiple comparisons when evaluating the primary endpoint, 24 h ketobemidone consumption, the Bonferroni Holm 19 correction was applied. The x 2 test or Fisher s exact test when appropriate was used for categorical variables and odds ratio (OR) with normal approximated 95% CI was calculated. Owing to some missing values, a mixed model with autoregressive covariance structure was used to analyse pain on incision, deep pain, and pain on coughing, and also for assessment of sedation, P Emax, and when analysing dimensions of SF-36. Study groups and time points were fixed effects and patients were random effect in this mixed model. None of the mixed models used found an overall statistically significant difference between study groups. The estimated marginal mean differences between groups at different time-points with 95% CI and P-values are presented. When normality assumption was not valid, and log transformation did not help, sensitivity analysis was performed using the Mann Whitney U-test, but because no different conclusions could be made from the analyses, these results are not presented. Two-tailed P-value of,.5 was considered to be statistically significant. All statistical analyses were performed using the SPSS version 17 (Chicago, IL, USA). Results Of the 4 patients initially randomized into the study, no patient was excluded and all patients completed the study (Fig. 1). The patient characteristic data in the two groups, the operation performed, and intraoperative fentanyl consumption are shown in Table 1. The rescue analgesic ketobemidone consumption was statistically significantly greater in compared with during 24 h and during 4 h after operation (Table 2). No significant difference in ketobemidone consumption was seen between the groups during the time period h. The number of patients given NSAID as rescue medication during 24 h did not differ significantly between the groups (Table 2). The intensity of postoperative pain on the NRS is shown in Figure 2A C. In general, the median pain scores were,5 in all groups, except during coughing when the median scores 33

4 Intraperitoneal local anaesthetics for pain relief after abdominal hysterectomy BJA Total number of patients operated during the study time period: 15 patients Did not fulfil inclusion criteria or had one of the exclusion criteria: 75 patients Number of patients interviewed for possible inclusion in the study: 75 patients Refused to participate Not able to understand study protocol because of language limitation: 35 patients Number randomized into the study: 4 patients (Patient-controlled i.p. analgesia): 2 patients (Continuous i.p. infusion): 2 patients Patients included for primary endpoint: 2 patients Patients excluded due to missing data for secondary endpoints in 1 3 patients* Patients included for primary endpoint: 2 patients Patients excluded due to missing data for secondary endpoints in 1 3 patients* Fig 1 Flow diagram of screened, excluded, and recruited patients. *See Tables for details. reached 7 in the early postoperative period. No significant differences were seen between the groups in NRS pain score at any time point during the 48 h study period. The total volume of levobupivacaine administered after the first 24 postoperative hours was statistically significantly lower in (18 ml) than in (24 ml) (P,.1). The recovery times and time to home-readiness are shown in Table 3. A statistically significant difference between the groups was found in the return of GI function, which was shorter in compared with. The mean time to home-readiness was statistically significantly shorter in compared with, while the length of hospital stay did not differ significantly between the groups. Expiratory muscle function, measured as maximum expiratory pressure (P Emax ), decreased at 4 h compared with preoperative values in both groups, and gradually recovered over time during 48 h. However, no statistically significant differences were found between the groups at any time point (Table 3). The incidence of PONV and the number of patients who received anti-emetics did not differ between the groups. The sedation scores between the groups were similar (Table 4) and no differences were seen between the groups in any of the parameters of the health-related quality of life (SF-36), or the average score in SF-36 at 1 or 3 months after surgery (Fig. 3). Discussion In this study, we found a statistically significant opioid-sparing effect when patients self-administered bolus doses of levobupivacaine compared with those having a continuous infusion of 331

5 BJA Perniola et al. LA. Furthermore, there was a faster return of GI function and a shorter time to home-readiness when intermittent injection of LA was used. Pain after abdominal hysterectomy arises from several structures that are traumatized during surgery 8 and includes somatic pain from the incision site, and pain from deeper structures including muscle pain and peritoneal and visceral pain. Although the magnitude of pain from each component is difficult to define, pain from the incision site is often relatively mild in comparison with deeper pain from the muscles and peritoneum. 212 Specifically, pain on mobilization and during coughing is multifactorial and can be very severe in the early postoperative period. 2 We studied patients undergoing abdominal hysterectomy since this is a procedure associated with moderate-to-severe postoperative pain, specifically in the early postoperative period. 221 We found a low supplementary analgesic consumption during the first 24 h after i.p. administration of levobupivacaine in both groups, confirming our previous studies Table 1 Patient characteristic data, duration of anaesthesia and operation, and fentanyl consumption are shown as mean (SD) except age (range). All other data are shown as numbers (ASA physical status) or n (%) as appropriate., patient-controlled i.p. analgesia;, continuous i.p. analgesia (n52) (n52) Age (yr) 48 (38 65) 51 (4 63) Weight (kg) 73 (12) 68 (9) Height (cm) 168 (5) 165 (6) ASA physical status (I/II) 15/5 17/3 Duration of operation (min) 119 (26) 121 (29) Duration of anaesthesia (min) 156 (27) 156 (29) Type of operation Total hysterectomy 12 (6%) 15 (75%) Salpingo-oophorectomy 8 (4%) 5 (25%) Type of incision Pfannenstiel 3 (15%) 4 (2%) Lower midline 17 (85%) 16 (8%) Intraoperative fentanyl (mg) 318 (74) 277 (75) However, we also found that PCipA has an advantage over continuous infusion in that supplementary analgesic consumption was further reduced by as much as 35% (from 36 to 23 mg) during 24 h. This was much lowerthan in one study where the 24 h mean morphine consumption, even with ibuprofen, was 47.3 mg. 21 Although we achieved good analgesia at the incision site by LA infiltration, several other components of pain may persist including muscle, peritoneal, and visceral pain. Recent studies, including two meta-analyses of the literature, have shown that i.p. administration of LA reduces postoperative pain after abdominal surgery. 822 Although the mechanism for improved analgesia with patient-controlled bolus doses could be speculative, we believe that the analgesic efficacy of continuous infusions may be partly due to their systemic absorption, and thereby a central rather than a local effect. Significant plasma concentration of LA is reached when they are infused intraperitoneally 2 and this may produce some analgesia by central mechanisms similar to i.v. infusion In contrast to continuous infusion, the analgesic efficacy of PCipA may be via localanti-inflammatoryeffects, 825 and alsobyblockingafferent sensory nerves transmitting visceral pain through the vagus nerves. 26 Thus, blocking of visceral pain by the intermittent injection of i.p. LA may not only result in decreased analgesic consumption, as in our present study, but even faster recovery of visceral functions such as the earlier return of bowel function, possibly due to lower rescue opioid consumption. This is an interesting hypothesis, supported by some evidence from the literature. In a recent study, infusion of i.p. ropivacaine after colectomy improved early surgical recovery. 27 The authors hypothesized that LA cause a transient chemical afferentectomy when injected intraperitoneally thereby producing analgesia and early functional recovery. However, the question that still remains unanswered from our present study is whether the analgesic effect of LA after PCipA is a systemic effect or a local analgesic and anti-inflammatory effect. In our present study, patients having PCipA with LA selfadministered 18 ml of levobupivacaine while those in the continuous group received 24 ml during the first 24 h after operation and yet had lower rescue analgesic consumption, which may also support a local effect. It is also possible, although speculative, that 1 ml of LA injection during 1 min in the PCipA group resulted in a wider spread of i.p. LA resulting Table 2 Analgesic consumption. All data are shown as mean (SD) except number of patients n (%) for NSAIDs. Data are analysed by the unpaired t-test or Fisher exact test as appropriate., patient-controlled i.p. analgesia;, continuous i.p. analgesia. *A mean ratio is the difference between two means on a relative scale, that is, mean ratio of 1.56 interprets as 56% higher geometric mean in compared with. Following the Bonferroni Holm correction for multiple comparisons, for details, see text. vs P; results are presented as odds ratio (95% CI) (n52) (n52) P, mean difference (95% CI) /P, mean ratio* (95% CI) P-values Ketobemidone in mg 4 h (range) 13.4 (7.1) (4 28) 21. (12.6) (8 59) 7.6 ( ) 1.56 ( ) Ketobemidone in mg 24 h (range) 23.1 (13.8) (8 48) 35.7 (2.2) (1 81) 12.6 ( ) 1.58 ( ) Ketobemidone in mg h 3.1 (4.2) ( 12) 6.3 (8.6) ( 31) 3.2 ( ) 1.84 ( ).6.6 (range) NSAID ( 24 h) [n (%)] 3 (15%) 4 (22%) 1.4 ( ) 1. Corrected P-values 332

6 Intraperitoneal local anaesthetics for pain relief after abdominal hysterectomy BJA A 1 8 B 1 8 NRS ( 1) 6 4 NRS ( 1) Hours Hours C 1 8 NRS ( 1) Hours Fig 2 (A C) Pain at the incision site, deep pain, and pain on coughing. Distributions are shown as box plots and inter-quartile range (IQR)., patient-controlled i.p. analgesia;, continuous i.p. infusion; NRS, numeric rating scale; circle, outliers. The whiskers represent minimum and maximum values if outliers are not present. in a block of more free afferent nerve endings within the peritoneum compared with a continuous infusion of 1 ml over 6 min. The reason why patients in both groups reported moderate to severe pain on coughing when they could request further analgesia (LA or opioids) is unclear. It is possible that analgesic supplementation was requested only during pain at rest and not during mobilization/coughing. Additionally, in our experience, some patients may have severe nausea or vomiting from opioid supplementation and accept pain on coughing rather than constant nausea. 28 The health-related quality-of-life questionnaire (SF-36) did not show any differences between the groups after operation, which may be not surprising since we did not find any difference in postoperative pain intensity between the groups. The faster recovery of GI function in patients receiving LA via PCipA may have resulted in a shorter time to home-readiness. The shortened time to recovery of bowel function after patientcontrolled i.p. administration of LA may be due to the opioid sparing which was evident in the present study. We found no major complications when using i.p. LA, including infection, 333

7 BJA Perniola et al. Table 3 Postoperative functional recovery and respiratory function. All data are shown as mean (SD) unless otherwise shown and analysed by the unpaired t-test except P Emax which was analysed by using mixed model. P Emax, maximum expiratory pressure;, patient-controlled i.p. analgesia;, continuous i.p. analgesia; GI, gastrointestinal (n52) (n52) vs P, mean difference (95% CI) P-values Time to walk with help (h) 21 (4), n¼19 22 (3), n¼19.4 (21.8 to 2.8).68 Time to walk without help (h) 23 (6), n¼19 25 (6), n¼ (22.1 to 6.6).3 Time to start drinking (h) 16 (7), n¼17 15 (8), n¼ (26.8 to 3.9).58 Time to start eating (h) 24 (9), n¼19 26 (8), n¼ (24.2 to 7.6).56 Home-readiness (days) 1.9 (.7), n¼ (1), n¼13.7 (.3 1.5).4 Length of hospital stay (days) 3.9 (.8), n¼2 4.5 (1.3), n¼2.6 (2.6 to 1.3).7 Return to GI function (days) 1.5 (.6), n¼ (.6), n¼18.7 (.2 1.2),.1 P E max (litre min 21 ) Before operation 59 (16), n¼17 6 (14), n¼18 4 h 35 (13), n¼18 34 (16), n¼19 21(21 to 7) h 42 (16), n¼19 34 (11), n¼2 27(216 to 1).9 48 h 45 (15), n¼19 41 (1), n¼19 24(213 to 5).37 Table 4 Side-effect and complications. All results are shown as number of patients n (%) except sedation which is presented as mean (SD). PON, postoperative nausea; POV, postoperative vomiting. The x 2 test or Fisher exact test was used as appropriate except sedation which was analysed using mixed model. NE, not estimated;, patient-controlled i.p. analgesia;, continuous i.p. analgesia. * vs P is presented as mean difference (95% CI) (n52) (n52) vs P, odds ratio (95% CI) P-value Postoperative nausea (PON) 4 h 1 (5%) 5 (25%).3 (.1 1.3) h 2 (1%) 2 (1%) 1. (.1 7.9) h 1 (5%) NE 1. Postoperative vomiting (POV) 4 h 3 (15%) 1 (5%).3 (.3 3.1) h 2 (1%) 1 (5%).5 (.4 5.6) h NE Total PON or POV 48 h 11 (55%) 6 (3%).3 (.1 1.3).11 Anti-emetics given ( 24 h) 16 (8%) 17 (85%) 1.4 (.3 7.3) 1. Anti-emetics given (24 48 h) 4 (2%) 3 (15%).7 (.1 3.6) 1. Sedation (NRS)* 4 h 4.8 (2.5), n¼ (2.7), n¼ (22.2 to 1.4) h 4. (2.4), n¼ (3.2), n¼2.4 (21.3 to 2.2) h 3.5 (3.), n¼ (2.4), n¼ (22.1 to 1.6).77 and no patient had any signs or symptoms of LA toxicity, which is in accordance with our earlier studies. 212 Study limitations The patient-controlled i.p. analgesia group received more intraoperative fentanyl, and therefore, the reduction in the 4 ketobemidone consumption in this group may reflect on the higher intraoperative fentanyl given. Furthermore, the wide CI of ketobemidone consumption during the first 24 h suggests caution in concluding that the primary endpoint of this study was clinically significant. However, the finding that some secondary endpoints such as return of GI function and home-readiness favour the patient-controlled i.p. method would suggest that there is some impact of reduced opioid consumption on recovery parameters. We did not measure plasma concentration of levobupivacaine in this study, which would be of interest in understanding the mechanism of action of LA. The PCipA with LA made it almost impossible to correctly schedule blood sampling. However, in our earlier study using higher doses of levobupivacaine via continuous i.p. infusion, we found a dose-dependent increase in plasma concentration 334

8 Intraperitoneal local anaesthetics for pain relief after abdominal hysterectomy BJA Preop Score month after surgery months after surgery PF RP BP GH VT SF RE MH PCS MCS Fig 3 Health-related quality of life (SF-36). Data are presented as mean of: physical functioning (PF), role-physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role-emotional (RE), mental health (MH); physical component score (PCS), and mental component score (MCS)., patient-controlled i.p. analgesia;, continuous i.p. infusion. There were missing data for one patient in before operation. After operation, at 1 month, there were missing data for five and six patients and at 3 months, for three and five patients in Groups P and C, respectively. See text for details. but no systemic toxicity due to the low level of free LA in the plasma. Another limitation of this study was that we did not verify catheter position by contrast injection. Therefore, we do not know the exact position of the catheter tip or if there was catheter migration during mobilization. Finally, we did not use a patient-controlled analgesia pump intravenously, which allows the correct assessment of analgesic requirement after operation since it would have been difficult for patients to handle two PCA devices, one for i.p. LA and the other for i.v. injection of opioids as rescue medication. Conclusions We found that the patient-controlled i.p. analgesia with LA resulted in statistically significant lower ketobemidone consumption compared with continuous infusion both during the initial postoperative phase and during 24 h after operation. Because of the large confidence intervals in ketobemidone consumption, the clinical relevance for this is uncertain. However, the lower ketobemidone consumption did translate into quicker return of GI function and earlier home-readiness. Future studies should focus on identifying the mechanism of analgesic effect of LA administered intermittently intraperitoneally. Authors contributions A.P.: contributed towards designing the study, data collection, statistical analysis, and writing the manuscript. F.F.: contributed towards data collection and critical comments in the writing of the manuscript. A.M.: contributed towards all statistical analysis and discussion on presentation of results. K.A.: contributed towards designing the study, data confirmation, and critical comments in the writing of the manuscript. A.G.: contributed towards designing, data interpretation, and writing of the manuscript. 335

9 BJA Perniola et al. Acknowledgements We would like to thank the personnel in the operating theatres and those in the postoperative and gynaecological wards for their help and attention during the various phases of this study. Special thanks to Ingegärd Wilhelmsson for her help with the data collection and with patient recruitment. Declaration of interest None declared. Funding This study was supported partly by funds obtained from the Research Committee, Örebro County Council, Örebro, Sweden. References 1 Jacobson GF, Shaber RE, Armstrong MA, Hung YY. Hysterectomy rates for benign indications. Obstet Gynecol 26; 17: Perniola A, Gupta A, Crafoord K, Darvish B, Magnuson A, Axelsson K. Intraabdominal local anaesthetics for postoperative pain relief following abdominal hysterectomy: a randomized, double-blind, dose-finding study. Eur J Anaesthesiol 29; 26: White PF. The changing role of non-opioid analgesic techniques in the management of postoperative pain. 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