Comparison of intraperitoneal ropivacaine and bupivacaine for postoperative analgesia in dogs undergoing ovariohysterectomy

Accepted Manuscript Comparison of intraperitoneal ropivacaine and bupivacaine for postoperative analgesia in dogs undergoing ovariohysterectomy Carlotta Lambertini, Katharina Kluge, Marta Lanza-Perea, Rodolfo Bruhl-Day, Karin S. Kalchofner Guerrero PII:

S1467-2987(18)30178-8

DOI:

10.1016/j.vaa.2018.06.012

Reference:

VAA 293

To appear in:

Veterinary Anaesthesia and Analgesia

Received Date: 5 December 2017 Revised Date:

13 April 2018

Accepted Date: 19 June 2018

Please cite this article as: Lambertini C, Kluge K, Lanza-Perea M, Bruhl-Day R, Kalchofner Guerrero KS, Comparison of intraperitoneal ropivacaine and bupivacaine for postoperative analgesia in dogs undergoing ovariohysterectomy, Veterinary Anaesthesia and Analgesia (2018), doi: 10.1016/ j.vaa.2018.06.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Comparison of intraperitoneal ropivacaine and bupivacaine for postoperative analgesia in

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dogs undergoing ovariohysterectomy

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Carlotta Lambertini1, Katharina Kluge2, Marta Lanza-Perea2, Rodolfo Bruhl-Day 2, Karin S

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Kalchofner Guerrero 2

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Sopra 50, Ozzano dell’Emilia (BO), Italy, 40064

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University, St.George’s, Grenada. True Blue, St. George’s, Grenada.

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Department of Veterinary Medical Sciences, University of Bologna, Bologna, Italy. Via Tolara di

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Small Animal Medicine & Surgery Department, School of Veterinary Medicine, St George’s

K. Kluge: [email protected]

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M. Lanza-Perea: [email protected]

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Rodolfo Bruhl-Day: [email protected]

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KS. Kalchofner Guerrero: [email protected]

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Corresponding author: Carlotta Lambertini, Department of Veterinary Medical Sciences,

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University of Bologna, via Tolara di Sopra 50, Ozzano dell’Emilia (BO), Italy, 40064

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E-mail: [email protected]

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Tel. +39 051 2097550

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Fax +39 051 796892

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ACCEPTED MANUSCRIPT Running title: Intraperitoneal ropivacaine in dogs

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Acknowledgments

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Authors would like to thank Dr. Maia Smith, from School of Medicine, St Georges’s University, for

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her contribution with the statistical analysis. al analysis.

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Sources of funding

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This research did not receive any specific grant from funding agencies in the public, commercial, or

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not-for-profit sectors.

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Authors’ contributions

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CL performed data acquisition, analysis and interpretation, and drafted the paper; KK participated

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in the data’s acquisition and interpretation, revised the paper and helped in arranging the final

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version; MLP participated in the data’s acquisition and interpretation and revised the paper; RBD

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participated in the study design, participated in drafting the paper and approved the final version;

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KKG conceived the study, participated in the data’s acquisition and interpretation, revised the paper

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and approved the final version.

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Conflict of interest statement

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Authors declare no conflict of interest

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ACCEPTED MANUSCRIPT

Abstract

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Objective To compare postoperative analgesia following either intraperitoneal (IP)

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ropivacaine or bupivacaine in dogs undergoing ovariohysterectomy (OVH) in the scope

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of multimodal analgesia.

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Study design Prospective, randomized, blinded clinical study.

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Animals A total of 45 privately owned dogs undergoing OVH, aged 37 ± 28 months

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and weighing 11.3 ± 4.5 kg.

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Methods Dogs were premedicated with acepromazine (0.05 mg kg-1) and morphine (0.5

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mg kg-1) intramuscularly (IM). Anaesthesia was induced with alfaxalone and

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maintained with isoflurane in oxygen. Carprofen (4 mg kg-1) was injected

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subcutaneously (SC) after intubation. Dogs were randomly assigned to receive either

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bupivacaine (3 mg kg-1) or ropivacaine (3 mg kg-1) IP prior to complete closure of the

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linea alba. At 0.5, 1, 2, 4, 6, and 8 hours after extubation sedation and postoperative

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pain were assessed, using the short form of the Glasgow Composite Pain scale (GCPS-

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SF), a dynamic interactive visual analogue scale (DIVAS), and mechanical nociceptive

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threshold (MNT) measurement. Rescue morphine (0.2 mg kg-1) was administered in

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case of ≥ 5/20 or ≥ 6/24 in the GCPS-SF and/or > 40 mm in the DIVAS. Parametric

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data were compared using t-test; non-parametric data were analysed with the two-

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sample Wilcoxon test (p < 0.05).

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Results The GCPS-SF score was significantly higher in group R at T8. There was no

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other significant difference regarding sedation or analgesia between groups. Rescue

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analgesia was administered to 15 dogs (R: 9/22; B: 6/22), with no significant difference

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between groups. MNT values decreased in both groups at all time points when

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compared to baseline. No adverse effects were observed.

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ACCEPTED MANUSCRIPT Conclusions and clinical relevance Ropivacaine or bupivacaine IP in combination

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with morphine IM and carprofen SC provided comparable postoperative analgesia in

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dogs after OVH for 6 hours. However, the anaesthetic protocol used did not prevent the

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administration of rescue analgesia in 41 % of animals.

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Keywords canine, intraperitoneal analgesia, ropivacaine, bupivacaine, local anaesthesia.

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Introduction

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Intraperitoneal

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ovariohysterectomy (OVH) has been described as an effective technique for

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management of postoperative pain, with dogs receiving IP bupivacaine requiring less

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rescue analgesia compared to placebo treated dogs (Carpenter et al. 2004; Campagnol et

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al. 2012).

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Bupivacaine has been associated with life-threatening cardiovascular side effects,

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leading to the development of a newer local anaesthetic (LA) drug, ropivacaine

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(McClure 1996). Ropivacaine is an amide-type LA, structurally related to bupivacaine,

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but prepared as the S-enantiomer. In animal models, ropivacaine has delayed

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cardiotoxic and neurotoxic side effects and a wider margin of safety compared to

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bupivacaine at equipotent doses (Dony et al. 2000).

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To the authors’ knowledge there are no reports on the use of IP ropivacaine in dogs. The

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aim of our study was to compare the effect of IP administered ropivacaine and

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bupivacaine on postoperative pain in dogs undergoing OVH. We hypothesized that IP

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ropivacaine would provide comparable postoperative analgesia to IP bupivacaine

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administered at equivalent doses.

administration

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Materials and methods

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The study was approved by the Animal Care and Use Committee of the St. George’s

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University (IACUC-17001-R). Written informed owner consent was obtained for all

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dogs prior to the study.

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Animals

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ACCEPTED MANUSCRIPT A total of 45 private-owned healthy female dogs referred to our veterinary teaching

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hospital for OVH were included in the study. Breed, age and body weight were

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recorded. Dogs were considered healthy based on clinical examination and haemato-

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biochemical parameters. Dogs were excluded if they were aggressive, pregnant, painful

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from pre-existing conditions, undergoing additional procedures besides OVH or

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administered drugs that were considered to be contraindicated. Dogs were randomly

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assigned to receive either IP bupivacaine (group B) or ropivacaine (group R) using an

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online

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www.sealedenvelope.com).

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Preanaesthetic preparation

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Dogs were admitted to the veterinary facility at least one day before surgery. The day

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before surgery they underwent a thorough physical examination and the baseline

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mechanical nociceptive threshold (MNT) in newtons was assessed. A mechanical

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algometer (ProdPlus, probe tip 4 mm; Topcat Metrology Ltd, UK) with a force range of

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0.5–25 Newtons (N) and an accuracy ± 0.5 N was used by the same operator (CL),

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unaware of treatment designation, to apply pressure at three sites next to the midline.

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Increasing pressure was applied and stopped as soon as the dog showed a reaction (e.g.

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sudden movement away from the device, looking at the device, vocalization, increased

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abdominal tension or attempts to bite) or if the pressure reached 13 N. The mean of

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three measurements was used for statistical analysis.

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Anaesthesia and surgery

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Food was withheld overnight; access to water was provided until premedication. On the

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day of the surgery, dogs were premedicated with acepromazine 0.05 mg kg-1

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ACCEPTED MANUSCRIPT (Acepromazine, VetOne, Idaho, USA) and morphine 0.5 mg kg-1 (Morphine sulfate

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injection BP, Martindale Pharmaceuticals, UK) administered intramuscularly (IM).

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Twenty minutes later a catheter was placed in a cephalic vein and anaesthesia was

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induced with alfaxalone (Alfaxan; Dechra Veterinary Products SAS, France)

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administered intravenously (IV) to effect until endotracheal intubation was achieved.

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Anaesthesia was maintained with isoflurane (Fluriso; VetOne, ID, USA) in oxygen.

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Carprofen 4 mg kg-1 (Rimadyl; Zoetis, MI, USA) was administered subcutaneously

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(SC) after intubation. Lactated Ringer’s solution (Baxter Healthcare Corporation, IL,

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USA) was administered IV at the rate of 5-10 mL kg-1 hour-1 throughout anaesthesia.

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Intraoperative monitoring consisted of heart rate, respiratory rate, end-tidal carbon

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dioxide, haemoglobin oxygen saturation (SpO2), non-invasive blood pressure and body

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temperature.

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Third year veterinary students performed both the anaesthesia and the OVH via a

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midline approach, under the close supervision of a board-certified anaesthesiologist and

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an experienced clinical surgeon respectively. Prior to complete closure of the linea alba,

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the supervising anaesthesiologist administered IP 3 mg kg-1 bupivacaine 0.5% (group B;

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Marcaine; Hospira, IL, USA) or 3 mg kg-1 ropivacaine 0.75% (group R; Naropin;

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AstraZeneca, UK) diluted with sterile water to 0.5% prior to administration). The local

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anaesthetic was administered using an 18-gauge IV catheter deprived of the inner stylet

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and inserted at the cranial portion of the incision. At the end of the skin closure,

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isoflurane was discontinued. Surgery and anaesthesia duration, as well as any

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complications observed were recorded.

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Postoperative assessment

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At 0.5, 1, 2, 4, 6, and 8 hours after extubation, sedation and pain were assessed by the

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ACCEPTED MANUSCRIPT same operator (CL) who was unaware of treatment. The degree of sedation was

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assessed with a numerical sedation score ranging from 0 (no sedation) to 3 (profound

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sedation). For pain assessment, the following tools were used: a dynamic interactive

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visual analogue scale (DIVAS), the short form of the Glasgow composite pain scale

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(GCPS-SF), and the MNT device, as previously described, but with the maximum

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pressure limited to the highest baseline measurement for that animal.

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Rescue morphine (0.2 mg kg-1 IM) was administered if ≥ 5/20 or ≥ 6/24 points were

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reached in the GCPS-SF and/or if the DIVAS reached ≥ 40 mm. Data recorded after the

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administration of rescue analgesia were excluded from statistical analysis.

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112 Statistical analysis

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Sample size calculations were performed using computer software (G-power 3.1). An

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alpha error was set at 5% and the standard deviation was set at 1.8 GCPS-SF points.

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The analysis indicated that, to declare non-inferiority of ropivacaine compared with

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bupivacaine, 19 dogs in each group would be needed assuming a difference of 1.8 on

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the GCPS-SF as being significant (Morton et al. 2005).

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Data were analysed with MedCalc 6.3 (MedCalc Software, Belgium). Data were tested

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for normality using a Shapiro-Wilk test. Two-tailed t-test were used for analysis of

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parametric data (age, weight, duration of surgery, duration of anaesthesia, time to

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extubation); nonparametric data (MNT, DIVAS score and GCPS-SF score) were

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compared using the two-sample Wilcoxon test. Parametric data are presented as mean ±

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SD; nonparametric data are presented as median (range). Administration of rescue

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analgesia was compared using a Chi-square test. A p < 0.05 was considered statistically

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significant.

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ACCEPTED MANUSCRIPT Results

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A total of 44 dogs, of the 45 included, completed the study. One dog in group R had to

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be excluded from postoperative assessment because of severe dysphoria at recovery

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which required additional sedation. Demographic data, surgery and anaesthesia duration

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did not differ between groups. Over 90 % of dogs included were mixed-breed. The

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dogs’ age was 37 ± 30 (5-108) months and 37 ± 26 (7-96) months and the body weight

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was 10.8 ± 4.2 (3.6-18.9) kg and 11.7 ± 4.9 (4.2-25.4) kg in groups R and B,

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respectively. The anaesthesia duration was 184.9 ± 19.3 (152-221) minutes and 186.8 ±

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20.8 (135-225) minutes and the surgery time was 143.9 ± 16.8 (106-172) minutes and

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144.5 ± 21.1 (97-182) minutes in groups R and B, respectively.

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Sedation scores did not differ between groups; after T1, the sedation score was 0 in all

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dogs. The GCPS-SF score was significantly higher in group R compared to B at T8

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(p=0.03) (Fig. 1A). There was no difference in DIVAS (Fig. 1B) and MNT (Fig. 1C)

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between groups at any time point. The MNT was significantly lower at every time point

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for both groups compared to baseline values.

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Rescue analgesia was administered to 15 dogs overall (group R: 9/22; group B: 6/22),

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with no significant differences between groups. Rescue analgesia was administered at:

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T0.5: B, 5; R, 1; T1: R, 2; T4: R, 1; T6: B, 1; T8: R, 5. No adverse effects were

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observed.

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Discussion

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In this study, administration of IP ropivacaine in dogs undergoing OVH provided

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comparable postoperative analgesia to an equivalent dose of IP bupivacaine for six

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hours after surgery.

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ACCEPTED MANUSCRIPT In the present study, 41 % of dogs in group R and 27 % of group B required rescue

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analgesia. It seems surprising that the multimodal analgesic approach used in dogs

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undergoing OVH was not adequate in > 40% of patients, as reflected by the requirement

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of rescue analgesia. The most probable explanation for this is the fact that 3rd year

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students performed the surgeries; inexperienced surgeons affect their patients differently

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than experienced surgeons, increasing tissue trauma and anaesthesia duration

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(Michelsen et al. 2012). In addition, our results might reflect how painful OVH is for

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dogs. However, the results of our studies are higher than previously reported: in the

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study of Carpenter et al. (2004), 20% of dogs in the IP bupivacaine group required

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rescue analgesia; in another study, none out of 39 dogs receiving IP bupivacaine

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required any rescue analgesia during the 20 hour postoperative evaluation period

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(Kalchofner Guerrero et al. 2016). However, those authors used a higher cut-off for

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rescue analgesia than our study, and they discuss that 47 % of dogs would have required

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rescue analgesia within the first 2 hours after surgery if they had decreased their cut-off

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in GCPS by one point.

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In this study, most dogs of group B required rescue morphine at T0.5 whereas most

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dogs of group R required it at T8. There are no pharmacokinetic studies on ropivacaine

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and bupivacaine administered IP. In humans, a similar onset of sensory block after

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epidural administration of equal doses of the two drugs was observed (Crosby et al.

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1998). In dogs, when the two local anaesthetics were compared for brachial plexus

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block, the onset of the sensory block did not differ significantly, but a a significantly

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shorter duration of the full block with ropivacaine was reported (Sakonju et al. 2009).

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Assuming that the two drugs have a similar onset after IP administration and

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considering the time delay between IP administration and extubation in our study, both

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ACCEPTED MANUSCRIPT drugs should have been effective 30 minutes after extubation. Therefore, our results are

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interesting and unexpected, since ropivacaine seemed to be longer acting compared with

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bupivacaine. However, a larger study including more animals might show more

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significant results. We can rather assume that most dogs in group R received their

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rescue analgesic at T8 because of the shorter duration of action of ropivacaine as

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previously reported.

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In order to increase the robustness of pain evaluation, three different assessment

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methods were used, and all the measures were carried out by the same investigator who

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was unaware of group assignment (Holton et al. 2001). The GCPS-SF was the only pain

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scale able to find a difference at T8. Even though the MNT aims to increase the

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objectivity in pain assessment, the interpretation of the dog’s response depends on the

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operator. Moreover, learning and anticipation occurs in dogs undergoing repeated

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algometric readings, with significant impact on the results (Coleman et al. 2014). For all

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dogs in both groups we observed a significant decrease in median MNT at every time

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point when compared to baseline. These results suggest that neither bupivacaine nor

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ropivacaine IP administration could prevent primary hyperalgesia, as previously

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reported (Kalchofner Guerrero et al. 2016).

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Doses administered for ropivacaine and bupivacaine were 3 mg kg-1. It is controversial

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if equivalent doses of bupivacaine or ropivacaine provide the same analgesic effect. In

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humans, the relative potency of intrathecal administered bupivacaine to ropivacaine has

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been determined to be approximately 3:2 (Gautier et al. 1999). To our knowledge, there

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are no studies comparing the potency of IP administered bupivacaine and ropivacaine.

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However, we cannot exclude that using a higher dose of ropivacaine or a more

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concentrated solution would have led to a different result.

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ACCEPTED MANUSCRIPT This study has several limitations. First, data from dogs treated with rescue morphine

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were excluded from statistical analysis for the subsequent time points; the reduction of

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the number of animals per group might have underpowered the study and brought about

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the lack of differences. However, including those data might have biased the results. A

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larger study including more animals would have shown more significant differences.

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Second, prior to IP administration ropivacaine was diluted with sterile water in order to

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use the same concentration and the same volume for both drugs, this could have had an

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impact on the physico-chemical properties of the solution which we did not take into

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account.

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Conclusion

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Based on our findings, equivalent doses of ropivacaine and bupivacaine administered IP

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provide comparable postoperative analgesia in dogs undergoing OVH. However, the

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analgesic protocol used, consisting of morphine IM, carprofen SC and either

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ropivacaine or bupivacaine IP, did not prevent the administration of rescue analgesia in

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41 % of the cases.

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References

Campagnol D, Teixeira-Neto FJ, Monteiro ER et al. (2012) Effect of

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intraperitoneal or incisional bupivacaine on pain and the analgesic requirement after

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ovariohysterectomy in dogs. Vet Anaesth Analg 39, 426-430.

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Carpenter RE, Wilson DV, Evans AT (2004) Evaluation of intraperitoneal and

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incisional lidocaine or bupivacaine for analgesia following ovariohysterectomy in the

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dog. Vet Anaesth Analg 31, 46-52. Coleman KD, Schmiedt CW, Kirkby KA et al. (2014) Learning Confounds

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Algometric Assessment of Mechanical Thresholds in Normal Dogs. Vet Surg 43, 361-

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Crosby E, Sandler A, Finucane B et al. (1998) Comparison of epidural anaesthesia

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with ropivacaine 0.5% and bupivacaine 0.5% for caesarean section. Can J Anaesth 45,

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Dony P, Dewinde V, Vanderick B et al. (2000) The comparative toxicity of ropivacaine and bupivacaine at equipotent doses in rats. Anesth Analg 91, 1489-1492. Gautier PE, De Kock M, Van Steenberge A et al. (1999) Intrathecal ropivacaine for ambulatory surgery. Anesthesiology 91, 1239-1245.

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Holton L, Reid J, Scott EM et al. (2001) Development of a behaviour-based scale to measure acute pain in dogs. Vet Rec 148, 525-531. Kalchofner Guerrero K, Campagna I, Bruhl-Day R et al. (2016) Intraperitoneal

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bupivacaine with or without incisional bupivacaine for postoperative analgesia in dogs

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undergoing ovariohysterectomy. Vet Anaesth Analg 43, 571-578.

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Michelsen J, Heller J, Wills F et al. (2012) Effect of surgeon experience on

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ovariohysterectomy in the dog: a randomised trial. Aust Vet J 90, 474-478.

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Morton CM, Reid J, Scott EM et al. (2005) Application of a scaling model to

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establish and validate an interval level pain scale for assessment of acute pain in dogs.

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Am J Vet Res 66, 2154-2166. Sakonju I, Maeda K, Maekawa R, et al. (2009) Relative nerve blocking properties

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of bupivacaine and ropivacaine in dogs undergoing brachial plexus block using a nerve

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stimulator. J Vet Med Sci 71, 1279-1284.

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ACCEPTED MANUSCRIPT Figure 1 Postoperative pain evaluation in 44 dogs undergoing ovariohysterectomy using (A) the short form of the Glasgow composite pain scale (GCPS-SF), (B) the dynamic interactive visual analogue scale (DIVAS) and (C) the mechanical nociceptive

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threshold (MNT) using a mechanical algometer. Dogs received intraperitoneally ropivacaine (group R

) or bupivacaine (group B ----) intraoperatively before

complete closure of the linea alba. Dogs were evaluated the day before surgery (baseline

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for the MNT) and from 30 minutes (T0.5) up to for 8 hours (T8) after extubation. Data collected after administration of rescue analgesia were not considered for statistical

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evaluation. (#) Statistically significant different between groups, (*) statistically

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significant different compared with baseline (p < 0.05).

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