Effect of dexmedetomidine infusion on the analgesic duration of peripheral nerve blocks in dogs: a randomized clinical study

Effect of dexmedetomidine infusion on the analgesic duration of peripheral nerve blocks in dogs: a randomized clinical study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Effect of dexmedetomidine infusion on the analgesic duration of peripheral nerve blocks in dogs: a randomized clinical study Chiara Franco, Elena Batisti, Søren Boysen, Stefano Patroncini, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3925108/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 Jul, 2024 Read the published version in Scientific Reports → Version 1 posted 8 You are reading this latest preprint version Abstract The aim of this study was to evaluate whether a continuous rate infusion (CRI) of dexmedetomidine could prolong the analgesic effect of peripheral nerve blocks. Twenty client-owned dogs were enrolled and randomly divided into 2 groups. The DEX group received dexmedetomidine infusion at 1 mcg kg -1 h -1 , and the NaCl group received an equivalent volume infusion of saline. Sciatic, saphenous and obturator nerve blocks were performed using 0.1 mL kg -1 0.5% ropivacaine/block. Intraoperative fentanyl was administered if the heart rate and/or mean arterial pressure (MAP) increased >15% from the previous measurement, and vasopressors were administered if the MAP was ≤ 70 mmHg. Postoperative pain was assessed every hour using the Glasgow Composite Pain Scale (GCPS). Postoperative rescue analgesia consisted of methadone (0.2 mg kg -1 IV) and carprofen (2 mg kg -1 IV). A greater number of dogs in the NaCl group required fentanyl (5/10 p= 0.03) and vasopressors (8/10, p=0.02) than did those in the DEX group (0/10 and 2/10, respectively). The duration of postoperative analgesia was significantly longer (604 ± 130 minutes) in the DEX group than in the NaCl group (400 ± 81 minutes, p=0.0005). Dexmedetomidine infusion at 1 mcg kg -1 h -1 reduces intraoperative analgesic and vasopressor requirements during orthopedic surgery and prolongs the postoperative analgesic effect of nerve blocks. Health sciences/Health care Health sciences/Medical research Health sciences/Medical research/Study design/Randomized controlled trials Figures Figure 1 Figure 2 Figure 3 Introduction The use of locoregional techniques in clinical practice has improved intra- and postoperative analgesia and decreased the dose of analgesics and anesthetics required during surgery 1 . Local anesthetics are widely used in veterinary medicine because they are effective and safe in most settings. To extend the duration of peripheral nerve blockade (PNB), several adjuvants, including opioids, alpha-2-agonists, epinephrine, phenylephrine, ketamine, and magnesium sulfate, have been added to local anesthetics 2 , 3 . Dexmedetomidine is an alpha-2-adrenergic agonist commonly used in veterinary medicine for its sedative, analgesic, and anesthetic-sparing effects. Its mechanism of action involves binding to alpha-2 receptors in the central and peripheral nervous systems, leading to sedation, analgesia, and other physiological effects. Studies in human medicine have reported a significantly shorter onset time of sensory and motor blockade when dexmedetomidine is administered perineurally 4 – 8 . This effect has only been partially and recently studied in veterinary medicine 9 – 12 . In 2017, Trein and colleagues reported that the administration of dexmedetomidine, perineurally or intramuscularly combined with perineural ropivacaine 0.75% (0.1 mL kg − 1 ), for femoral and sciatic nerve blocks did not significantly change the onset time of sensory or motor blockade or prolong the duration of motor blockade in dogs 9 . However, intravenous administration of dexmedetomidine at 1 mcg kg − 1 h − 1 and local lidocaine increased the duration of sensory sciatic and femoral nerve blockade and reduced the need for additional analgesia during the immediate postoperative period in dogs undergoing orthopedic surgery for tibial tuberosity advancement (TTA) 13 . Although the exact underlying mechanisms are not fully understood, there is evidence suggesting that dexmedetomidine, when administered intravenously, can potentially prolong the duration of peripheral sensory blocks and reduce the need for additional analgesics during the postoperative period. The primary aim of the present study was to evaluate whether a constant rate infusion (CRI) of dexmedetomidine at a dose of 1 mcg kg − 1 h − 1 can reduce intraoperative fentanyl requirements and prolong the duration of analgesic efficacy with saphenous, sciatic and obturator nerve blockade. The secondary aim of the study was to evaluate whether dexmedetomidine infusion can reduce the administration of intraoperative vasopressors. Our hypothesis is that a CRI of dexmedetomidine can reduce the need for systemic analgesic and vasoactive drugs during elective surgical procedures and prolong the duration of peripheral sensory blockade. Materials and methods Study design This prospective randomized blinded study was conducted at the Veterinary Teaching Hospital of the University of Pisa. The study received approval by the Ethical Committee for animal welfare of University of Pisa (n = 22/2020), and the study included dogs undergoing orthopedic surgery. All methods were carried out in accordance with relevant guidelines and regulations for studies involving animal and in accordance with ARRIVE guidelines. The study did not involve humans. Animals To identify a difference of at least 120 minutes between the 2 groups, the median duration of nerve blocks was estimated at 480 minutes, and an α error of 0.05 and a β error of 0.2 were used; the minimum number of dogs necessary for each group was 7. To account for higher than expected values, standard deviations and data loss of up to 30%, the number of dogs in each group was increased to 10. All dogs had a complete physical examination and full bloodwork (complete blood count, plasma biochemistry panel, and coagulation test) at hospital admission. The exclusion criteria included a C-reactive protein (CRP) level > 0.3 mg dL − 1 , an albumin concentration 13 years of age, a diagnosis of malignancy, an aggressive disposition, skin infections, or the inability to secure vascular access before premedication. Study protocol All dogs were randomly divided into two groups according to the use of an online software program (random.org): the dexmedetomidine group (DEX) and the saline group (NaCl). The dexmedetomidine group received a CRI of dexmedetomidine at 1 mcg kg − 1 h − 1 , while the control group received an equivalent volume infusion of 0.9% saline solution. The infusion syringes, which were only labeled with the patient identification number, were prepared by an operator not directly involved in the study. On the day of surgery, a peripheral venous catheter was placed (cephalic or saphenous) to facilitate CRI administration. The CRIs (dexmedetomidine or saline) were started 10 minutes prior to anesthetic induction and discontinued at the end of anesthesia. Ten minutes after the start of the CRI, all dogs received 0.2 mg kg − 1 IV methadone (Semfortan, 10 mg mL − 1 ; Dechra, Turin, Italy) and were induced with propofol (Proposure, Boehringer Ingelheim Animal Health, Italy S.p.A.) to achieve orotracheal intubation. Patients were connected to an anesthetic machine (Avance CS2 Pro, GE, Milan, Italy) by a rebreathing system and maintained on isoflurane (Vetflurane, Virbac S.r.l., Milan, Italy) in oxygen at an inspired fraction of 70%. All patients were ventilated using volume-controlled settings with a tidal volume of 10 mL kg − 1 and a variable respiratory rate targeted to maintain an end-expiratory carbon dioxide (PE’CO 2 ) value between 35 and 45 mmHg. To combat intraoperative atelectasis, positive end-expiratory pressure (PEEP) was set at 5 cm H 2 O. Patients were positioned in lateral recumbency with the target leg to block in the nongravity-dependent position, and after trichotomy and surgical resection of the region, nerve blockade was performed. Ultrasound-guided sciatic, saphenous and obturator nerve blocks were performed as previously described 14 – 16 using 0.1 mL kg − 1 0.5% ropivacaine (Naropina; AstraZeneca, Verona, Italy). All blocks were performed using an in-plane visual axis technique 17 with a dedicated echogenic needle (Visioplex, Vygon Italia S.r.l., Padua, Italy) and a linear transducer (HFL50, 15–6 MHz Linear Transducer). Operators performing blocks and clinicians monitoring patients throughout the intra- and postoperative periods were blinded to the study CRI administered. In the event nociception was suspected based on an increase in heart rate and/or mean arterial pressure (MAP) greater than 15% above previous measurements 18 , a bolus of fentanyl 1 mcg kg − 1 (Fentadon, 50 mcg mL − 1 , Eurovet Animal Health B.V., Bladel, The Netherlands) was administered, and if considered insufficient, a variable dose of fentanyl CRI was initiated. If dogs experienced hypotension (MAP < 70 mmHg), dopamine (Dopamina Hospira, 200 mg mL − 1 ; Hospira Italia, Naples, Italy) was administered, which was replaced by norepinephrine (Noradrenalina tartato 2 mg mL − 1 ; S.A.L.F.). S.p.A. Bergamo, Italy) if dopamine failed to correct the hypotension within 5 minutes. During surgery, heart rate (HR), arterial blood pressure, capillary refill time (CRT), ECG rhythm, end-tidal CO 2 (PE’CO 2 ), fraction of expired isoflurane (F e ’Iso) and spirometry were recorded every five minutes (Avance CS 2 Pro, GE, Milan, Italy) and at specific surgical time points (Table 1 ). The dexmedetomidine or NaCl CRI was discontinued when inhalant anesthesia was stopped. The need and dose of any analgesic (fentanyl) and/or vasoactive drugs (dopamine, norepinephrine) administered were also recorded. Postoperative pain was assessed every hour starting from the time of extubation using the Glasgow Composite Pain Scale (GCPS); if the pain score was greater than 6 of 24 or 5 of 20, methadone was administered at 0.2 mg kg − 1 IM (Semfortan, 10 mg mL − 1 ; Dechra, Turin, Italy), and carprofen was administered at 2 mg kg − 1 IV (Rimadyl, 50 mg mL − 1 ; Zoetis Italia S.r.l., Rome, Italy). Table 1 Data recording time points Time Procedure T0 five minutes prior to surgical draping T1 surgical draping T2 skin and subcutaneous tissue incision T3 drilling T4 tibial osteotomy T5 plate fixation T6 skin and subcutaneous tissue closure The postoperative analgesic requirements and possible side effects and complications during hospitalization and at the surgical follow-up were recorded. Statistical analysis The data were analyzed for normality using D'Agostino and Pearson tests and a commercial software program (Prism 9; GraphPad Prism, Inc.). Parametric data are expressed as the mean and standard deviation, while nonparametric data are expressed as the median and range. Student's t test and the Mann‒Whitney test were used to compare parameters between groups. One-way ANOVA with Dunnett's post hoc test was used to compare values within groups over time. A chi-square test was used to compare groups requiring rescue analgesia and vasopressors. P values < 0.05 were considered to indicate statistical significance. Results Twenty dogs were enrolled and completed the study uneventfully. The mean weight and age did not differ between the groups: 30 ± 12 kg (NaCl) and 32 ± 13 kg (DEX), 6.3 ± 2.5 years (NaCl) and 7.8 ± 2.7 years (DEX). Intraoperative administration of fentanyl was required in 5/10 dogs in the NaCl group and 0/10 dogs in the DEX group (p = 0.03). A significantly greater number of dogs in the NaCl group (8/10) required vasopressors (p = 0.02) than did those in the DEX group (2/10). The heart rate was significantly lower in the DEX group than in the NaCl group (p < 0.0001) throughout the entire treatment period (Fig. 1 ). There were no significant differences in systolic or mean arterial pressure (SAP or MAP), F e ’Iso (Figs. 2 and 3 ), temperature, saturation of peripheral oxygen (SpO 2 ), or PE’CO 2 between the groups. The duration of postoperative analgesia was significantly longer (604 ± 130 minutes) in the DEX group than in the NaCl group (400 ± 81 minutes) (p = 0.0005). All the dogs recovered uneventfully, with no complications noted during follow-up evaluation at 24 hours, 7 days, 14 days or 30 days after surgery. Discussion This study confirmed that the administration of a 1 mcg kg − 1 h − 1 dexmedetomidine CRI in dogs undergoing TTA surgery prolongs the duration of postoperative analgesia and reduces the requirement for intraoperative analgesics and vasopressors. The mechanism through which dexmedetomidine enhances the efficacy of peripheral nerve blockade is uncertain and may differ if given intravenously or locally. Brummett and colleagues evaluated the activity of alpha-2-adrenergic agonists administered perineurally in combination with local anesthetics; they hypothesized that the synergistic effects of dexmedetomidine are likely due to the increased blockade of the hyperpolarization-activated cation current and not to agonism of the alfa-2-adrenoceptor. In that study, dexmedetomidine was administered locally (perineural), and the authors concluded that the effects were peripheral and not due to centrally mediated or systemic analgesia 19 . It has also been proposed that dexmedetomidine-induced vasoconstriction may decrease the plasma absorption of locally administered anesthetic agents, subsequently leading to a prolonged and increased concentration of local anesthetic available to nerve fibers. This hypothesis is supported by the findings of a study in which the plasma concentration of bupivacaine administered intraperitoneally was similar between groups when the anesthetic was administered with either dexmedetomidine or adrenaline 20 . Another option is the supraspinal action of dexmedetomidine; the alpha-2 receptor binds to the locus coeruleus in the brainstem, decreases the release of norepinephrine, inhibits sympathetic activity and action at the dorsal horn, and alters the modulation of nociceptive signals 19 . Our study showed that a 1 mcg kg − 1 h − 1 CRI of dexmedetomidine in dogs prolonged the duration of postoperative peripheral nerve blockade and delayed the need to administer postoperative opioids. This finding suggested that dexmedetomidine selectively prolongs sensory blockade over motor blockade, a finding that has also been suggested previously in human medicine 21 . In veterinary medicine, a recent study revealed that an IV infusion of dexmedetomidine prolongs the duration of perineural lidocaine sensory blockade without impacting motor function 13 . Dexmedetomidine infusions have also been demonstrated to increase sensory blockade without significantly impairing motor function or causing bradycardia when given IV during bupivacaine-induced spinal anaesthesia 22 . Interestingly, that same study revealed that dexmedetomidine infusions increased the analgesic duration of bupivacaine-induced spinal anesthesia by approximately 50 minutes 22 . In our study, dogs that received a dexmedetomidine CRI did not require rescue analgesia during surgery, suggesting that the dose used, in combination with the nerve blocks, is helpful for covering intraoperative analgesia during TTA. In fact, it is possible that the dose of 1 mcg kg − 1 h − 1 dexmedetomidine CRI fills any “analgesic holes” not covered by regional blockade, thus contributing to a multimodal analgesic approach. These findings are similar to those of Lovell and colleagues, who compared the analgesic efficacy of fentanyl alone to that of dexmedetomidine/ketamine infusion and suggested that the use of dexmedetomidine and ketamine might be a valid alternative for treating opioid-free aesthesia, as no significant differences in pain management were reported between the two groups 23 . There are several reasons that may explain the reduced need for intraoperative analgesia in dogs receiving a dexmedetomidine CRI, which are widely discussed in human and veterinary medicine 24 – 26 . In our study, the DEX group had a lower heart rate (HR) and required significantly less vasopressor administration than did the NaCl group. The effects of dexmedetomidine on the cardiovascular system are well known, with bradycardia, increased peripheral resistance and decreased cardiac output being the most important. The reason why a lower DEX concentration is associated with a lower requirement for vasopressors is not fully understood, and several mechanisms have been proposed to explain how alpha-2 agonists improve vasopressor responsiveness. Pichot et al suggested that dexmedetomidine can reduce the downregulation of alpha-1 receptors and/or produce gradual resensitization of alpha-1 adrenergic receptors by reducing the sympathetic outflow and release of endogenous catecholamines observed in patients with sepsis 27 , 28 . It has also been proposed that α-2 agonists may act on vascular smooth muscle cells via local mechanisms, and the presynaptic action of α-2 agonists could, by reducing the release of endogenous noradrenaline, lead to the upregulation of postsynaptic α-1 receptors 28 – 30 . Although the potential benefit of dexmedetomidine in decreasing vasopressor administration has been studied in several human clinical settings 28 , 31 its clinical effect on hemodynamic variables in veterinary patients is lacking. That said, the effects of the dexmedetomidine CRI found in the current study agree with the cardiovascular effects reported in two experimental studies in dogs undergoing anesthesia 32 , 33 . Our study has some limitations. The ideal CRI dosage of dexmedetomidine required to provide analgesia is not well known and varies within the veterinary literature. The most frequently reported doses range from 0.5 to 1 mcg kg − 1 h − 1 and are administered alone or in combination with other drugs as a CRI 13 , 22 , 23 . However, it has been suggested that a CRI dosage of 3 mcg kg − 1 h − 1 is necessary in some cases to achieve an algesia effect in dogs and that 1 mcg kg − 1 h − 1 CRI doses provide only a sedative effect 34 . Finally, two operators with different levels of experience performed the peripheral nerve blocks, which may have introduced bias regarding the success and duration of peripheral nerve blockade. However, two operators were more reflective of clinical practice, as different clinicians are required to cover anesthesia shifts and subsequently perform nerve blocks. Conclusion The current study confirmed that a CRI of dexmedetomidine of 1 mcg kg − 1 h − 1 can prolong the analgesic effects of peripheral nerve blockade in dogs by approximately 2 hours. Dexmedetomidine infusions can also reduce the intraoperative need for supplemental analgesia and vasopressor administration. Further studies using different dexmedetomidine CRIs and enrolling more patients are recommended. Declarations Author contributions: CDF, AB: study design, data management, data interpretation, statistical analysis and preparation of manuscript. EB, SP and EA: study design, data management, and preparation of manuscript. SB: study design, data interpretation, preparation and revision of the manuscript. The datasets used and/or analysed during the current study available from the corresponding author on reasonable request. Funding This research received no external funding. Competing interests The authors declare no competing interests. Author Contribution CDF, AB: study design, data management, data interpretation, statistical analysis and preparation of manuscript.EB, SP and EA: study design, data management, and preparation of manuscript.SB: study design, data interpretation, preparation and revision of the manuscript. References Helb, J.R. et al. A preemptive multimodal pathway featuring peripheral nerve block improves perioperative outcomes after major orthopedic surgery. Reg. Anesth. Pain Med . 33, 510-517 (2008). Axelsson, K., Gupta, A. Local Anesthetics adjuvants: neuraxial versus peripheral nerve block. Curr. Opin. Anaesth. 22:649-654. (2009). Adami, C. et al. 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Comparison of the efficacy of two doses of dexmedetomidine as an adjunct to levobupivacaine in infraclavicular brachial plexus block: prospective double-blinded randomized controlled trial. BMC Anesthesiol . 22:338 (2022). Trein T.A. et al. Effects of dexmedetomidine combined with ropivacaine on sciatic and femoral nerve blockade in dogs. Vet Anaesth Analg. 44:144-153 (2017). Acquafredda, C. et al. Clinical efficacy of dexmedetomidine combined with lidocaine for femoral and sciatic nerve blocks in dogs undergoing stifle surgery. Vet Anaesth Analg . 48:962-971 (2021). Marolf, V. et al. Effects of perineural administration of ropivacaine combined with perineural or intravenous administration of dexmedetomidine for sciatic and saphenous nerve blocks in dogs. Am J Vet Res . 82:449-458 (2021). Marolf, V. et al. Effects of perineural dexmedetomidine combined with ropivacaine on postoperative methadone requirements in dogs after tibial plateau levelling osteotomy: a two-center study. 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Cite Share Download PDF Status: Published Journal Publication published 24 Jul, 2024 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 02 Apr, 2024 Reviews received at journal 25 Mar, 2024 Reviewers agreed at journal 22 Mar, 2024 Reviewers invited by journal 22 Mar, 2024 Editor assigned by journal 19 Mar, 2024 Editor invited by journal 20 Feb, 2024 Submission checks completed at journal 20 Feb, 2024 First submitted to journal 03 Feb, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3925108","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":273956655,"identity":"651c6d9e-16bf-4723-a4f9-5f2496269359","order_by":0,"name":"Chiara Franco","email":"","orcid":"","institution":"University of Pisa","correspondingAuthor":false,"prefix":"","firstName":"Chiara","middleName":"","lastName":"Franco","suffix":""},{"id":273956656,"identity":"6584fd0d-7321-4dc4-95d1-03575aec827b","order_by":1,"name":"Elena Batisti","email":"","orcid":"","institution":"University of Pisa","correspondingAuthor":false,"prefix":"","firstName":"Elena","middleName":"","lastName":"Batisti","suffix":""},{"id":273956657,"identity":"29fd5366-f76b-484f-940d-2c58ad0a1d68","order_by":2,"name":"Søren Boysen","email":"","orcid":"","institution":"University of Calgary","correspondingAuthor":false,"prefix":"","firstName":"Søren","middleName":"","lastName":"Boysen","suffix":""},{"id":273956658,"identity":"f36bc7f3-0433-4fed-8194-c8dbeb828863","order_by":3,"name":"Stefano Patroncini","email":"","orcid":"","institution":"University of Pisa","correspondingAuthor":false,"prefix":"","firstName":"Stefano","middleName":"","lastName":"Patroncini","suffix":""},{"id":273956659,"identity":"1812e0f8-846e-4ff6-8ff2-0708f1ec4426","order_by":4,"name":"Emanuele Alessandroni","email":"","orcid":"","institution":"University of Pisa","correspondingAuthor":false,"prefix":"","firstName":"Emanuele","middleName":"","lastName":"Alessandroni","suffix":""},{"id":273956660,"identity":"2696a5eb-45a5-4d0c-969e-91df888a4c12","order_by":5,"name":"Angela Briganti","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABBUlEQVRIie3RMWsCMRTA8VcO7pbgra9Y9CtEOlSoH+aFgllOodziUI6Dwt3W2dIv4VcohevSxS2gQ0RwFgQ5EIp3qW2hkHPtkP/0EviRhAC4XP81DUDgmRE7ABdptcRmQj+E8PqbNBtDTpNIT5tWEr7kc00PML7Jg/nuvuzL2eIx0xr6iY3g8iPmVEB89cbi9pRwNFu+5rzxYioaIvkgph6jNquJEhk2ka6KZEmfhtwdKiL5OcKVLEBkNQmK+hQ6S3oq8lA8YYwe82/ZEHvPSlRv4XiZWkhHydV2ux+MMXxfL9gg6baU3KzKSRJanw+Mw9cnmMHkVxe2A4BA/x1q4nK5XK7fjhzTUn8cRorcAAAAAElFTkSuQmCC","orcid":"","institution":"University of Pisa","correspondingAuthor":true,"prefix":"","firstName":"Angela","middleName":"","lastName":"Briganti","suffix":""}],"badges":[],"createdAt":"2024-02-03 19:29:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3925108/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3925108/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-024-67894-x","type":"published","date":"2024-07-24T16:15:53+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":51513174,"identity":"3d0d5078-9bd0-4e91-b703-090961d35a43","added_by":"auto","created_at":"2024-02-22 21:26:10","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":23709,"visible":true,"origin":"","legend":"\u003cp\u003eMean values and standard deviations of heart rate (HR) in the 2 groups at surgery; * significantly different from the NaCl group.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3925108/v1/90811422431e8f89cdf96da2.jpg"},{"id":51513175,"identity":"9fcb9b27-e3ac-4f00-ab78-2b16a682c68e","added_by":"auto","created_at":"2024-02-22 21:26:11","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":21651,"visible":true,"origin":"","legend":"\u003cp\u003eMean values and standard deviations of systolic and mean arterial pressure (SAP and MAP) in the 2 groups at surgery.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3925108/v1/f087c5db3428f19b6b836bc5.jpg"},{"id":51513173,"identity":"175531e4-f92a-4dab-9f92-37da52e35355","added_by":"auto","created_at":"2024-02-22 21:26:10","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":27883,"visible":true,"origin":"","legend":"\u003cp\u003eMean values and standard deviations of the expired fraction of isoflurane (Fe’Iso) in the 2 groups at surgery.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3925108/v1/86dbcea85893d3ad52a4996b.jpg"},{"id":61596416,"identity":"8dea4f4e-fa07-4ba6-ade2-97e73def44bf","added_by":"auto","created_at":"2024-08-01 17:27:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":430531,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3925108/v1/fedfb9ef-2385-41d9-ae3a-2204fc24016a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effect of dexmedetomidine infusion on the analgesic duration of peripheral nerve blocks in dogs: a randomized clinical study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe use of locoregional techniques in clinical practice has improved intra- and postoperative analgesia and decreased the dose of analgesics and anesthetics required during surgery\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Local anesthetics are widely used in veterinary medicine because they are effective and safe in most settings. To extend the duration of peripheral nerve blockade (PNB), several adjuvants, including opioids, alpha-2-agonists, epinephrine, phenylephrine, ketamine, and magnesium sulfate, have been added to local anesthetics\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eDexmedetomidine is an alpha-2-adrenergic agonist commonly used in veterinary medicine for its sedative, analgesic, and anesthetic-sparing effects. Its mechanism of action involves binding to alpha-2 receptors in the central and peripheral nervous systems, leading to sedation, analgesia, and other physiological effects. Studies in human medicine have reported a significantly shorter onset time of sensory and motor blockade when dexmedetomidine is administered perineurally \u003csup\u003e\u003cspan additionalcitationids=\"CR5 CR6 CR7\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. This effect has only been partially and recently studied in veterinary medicine\u003csup\u003e\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. In 2017, Trein and colleagues reported that the administration of dexmedetomidine, perineurally or intramuscularly combined with perineural ropivacaine 0.75% (0.1 mL kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e), for femoral and sciatic nerve blocks did not significantly change the onset time of sensory or motor blockade or prolong the duration of motor blockade in dogs\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eHowever, intravenous administration of dexmedetomidine at 1 mcg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e h\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e and local lidocaine increased the duration of sensory sciatic and femoral nerve blockade and reduced the need for additional analgesia during the immediate postoperative period in dogs undergoing orthopedic surgery for tibial tuberosity advancement (TTA)\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Although the exact underlying mechanisms are not fully understood, there is evidence suggesting that dexmedetomidine, when administered intravenously, can potentially prolong the duration of peripheral sensory blocks and reduce the need for additional analgesics during the postoperative period.\u003c/p\u003e \u003cp\u003eThe primary aim of the present study was to evaluate whether a constant rate infusion (CRI) of dexmedetomidine at a dose of 1 mcg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e h\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e can reduce intraoperative fentanyl requirements and prolong the duration of analgesic efficacy with saphenous, sciatic and obturator nerve blockade. The secondary aim of the study was to evaluate whether dexmedetomidine infusion can reduce the administration of intraoperative vasopressors. Our hypothesis is that a CRI of dexmedetomidine can reduce the need for systemic analgesic and vasoactive drugs during elective surgical procedures and prolong the duration of peripheral sensory blockade.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003eStudy design\u003c/p\u003e \u003cp\u003eThis prospective randomized blinded study was conducted at the Veterinary Teaching Hospital of the University of Pisa. The study received approval by the Ethical Committee for animal welfare of University of Pisa (n\u0026thinsp;=\u0026thinsp;22/2020), and the study included dogs undergoing orthopedic surgery. All methods were carried out in accordance with relevant guidelines and regulations for studies involving animal and in accordance with ARRIVE guidelines. The study did not involve humans.\u003c/p\u003e \u003cp\u003eAnimals\u003c/p\u003e \u003cp\u003eTo identify a difference of at least 120 minutes between the 2 groups, the median duration of nerve blocks was estimated at 480 minutes, and an α error of 0.05 and a β error of 0.2 were used; the minimum number of dogs necessary for each group was 7. To account for higher than expected values, standard deviations and data loss of up to 30%, the number of dogs in each group was increased to 10.\u003c/p\u003e \u003cp\u003eAll dogs had a complete physical examination and full bloodwork (complete blood count, plasma biochemistry panel, and coagulation test) at hospital admission.\u003c/p\u003e \u003cp\u003eThe exclusion criteria included a C-reactive protein (CRP) level\u0026thinsp;\u0026gt;\u0026thinsp;0.3 mg dL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, an albumin concentration\u0026thinsp;\u0026lt;\u0026thinsp;2.00 g dL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, a dog\u0026thinsp;\u0026gt;\u0026thinsp;13 years of age, a diagnosis of malignancy, an aggressive disposition, skin infections, or the inability to secure vascular access before premedication.\u003c/p\u003e \u003cp\u003eStudy protocol\u003c/p\u003e \u003cp\u003eAll dogs were randomly divided into two groups according to the use of an online software program (random.org): the dexmedetomidine group (DEX) and the saline group (NaCl). The dexmedetomidine group received a CRI of dexmedetomidine at 1 mcg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003eh\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, while the control group received an equivalent volume infusion of 0.9% saline solution. The infusion syringes, which were only labeled with the patient identification number, were prepared by an operator not directly involved in the study. On the day of surgery, a peripheral venous catheter was placed (cephalic or saphenous) to facilitate CRI administration. The CRIs (dexmedetomidine or saline) were started 10 minutes prior to anesthetic induction and discontinued at the end of anesthesia. Ten minutes after the start of the CRI, all dogs received 0.2 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e IV methadone (Semfortan, 10 mg mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e; Dechra, Turin, Italy) and were induced with propofol (Proposure, Boehringer Ingelheim Animal Health, Italy S.p.A.) to achieve orotracheal intubation. Patients were connected to an anesthetic machine (Avance CS2 Pro, GE, Milan, Italy) by a rebreathing system and maintained on isoflurane (Vetflurane, Virbac S.r.l., Milan, Italy) in oxygen at an inspired fraction of 70%.\u003c/p\u003e \u003cp\u003eAll patients were ventilated using volume-controlled settings with a tidal volume of 10 mL kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e and a variable respiratory rate targeted to maintain an end-expiratory carbon dioxide (PE\u0026rsquo;CO\u003csub\u003e2\u003c/sub\u003e) value between 35 and 45 mmHg. To combat intraoperative atelectasis, positive end-expiratory pressure (PEEP) was set at 5 cm H\u003csub\u003e2\u003c/sub\u003eO.\u003c/p\u003e \u003cp\u003ePatients were positioned in lateral recumbency with the target leg to block in the nongravity-dependent position, and after trichotomy and surgical resection of the region, nerve blockade was performed. Ultrasound-guided sciatic, saphenous and obturator nerve blocks were performed as previously described\u003csup\u003e\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e using 0.1 mL kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e 0.5% ropivacaine (Naropina; AstraZeneca, Verona, Italy). All blocks were performed using an in-plane visual axis technique\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e with a dedicated echogenic needle (Visioplex, Vygon Italia S.r.l., Padua, Italy) and a linear transducer (HFL50, 15\u0026ndash;6 MHz Linear Transducer). Operators performing blocks and clinicians monitoring patients throughout the intra- and postoperative periods were blinded to the study CRI administered.\u003c/p\u003e \u003cp\u003eIn the event nociception was suspected based on an increase in heart rate and/or mean arterial pressure (MAP) greater than 15% above previous measurements\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e, a bolus of fentanyl 1 mcg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (Fentadon, 50 mcg mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, Eurovet Animal Health B.V., Bladel, The Netherlands) was administered, and if considered insufficient, a variable dose of fentanyl CRI was initiated. If dogs experienced hypotension (MAP\u0026thinsp;\u0026lt;\u0026thinsp;70 mmHg), dopamine (Dopamina Hospira, 200 mg mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e; Hospira Italia, Naples, Italy) was administered, which was replaced by norepinephrine (Noradrenalina tartato 2 mg mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e; S.A.L.F.). S.p.A. Bergamo, Italy) if dopamine failed to correct the hypotension within 5 minutes.\u003c/p\u003e \u003cp\u003eDuring surgery, heart rate (HR), arterial blood pressure, capillary refill time (CRT), ECG rhythm, end-tidal CO\u003csub\u003e2\u003c/sub\u003e (PE\u0026rsquo;CO\u003csub\u003e2\u003c/sub\u003e), fraction of expired isoflurane (F\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ee\u003c/span\u003e\u0026rsquo;Iso) and spirometry were recorded every five minutes (Avance CS\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Pro, GE, Milan, Italy) and at specific surgical time points (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The dexmedetomidine or NaCl CRI was discontinued when inhalant anesthesia was stopped. The need and dose of any analgesic (fentanyl) and/or vasoactive drugs (dopamine, norepinephrine) administered were also recorded. Postoperative pain was assessed every hour starting from the time of extubation using the Glasgow Composite Pain Scale (GCPS); if the pain score was greater than 6 of 24 or 5 of 20, methadone was administered at 0.2 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e IM (Semfortan, 10 mg mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e; Dechra, Turin, Italy), and carprofen was administered at 2 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e IV (Rimadyl, 50 mg mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e; Zoetis Italia S.r.l., Rome, Italy).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eData recording time points\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eProcedure\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eT0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003efive minutes prior to surgical draping\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eT1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003esurgical draping\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eT2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eskin and subcutaneous tissue incision\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eT3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003edrilling\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eT4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003etibial osteotomy\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eT5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eplate fixation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eT6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eskin and subcutaneous tissue closure\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe postoperative analgesic requirements and possible side effects and complications during hospitalization and at the surgical follow-up were recorded.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe data were analyzed for normality using D'Agostino and Pearson tests and a commercial software program (Prism 9; GraphPad Prism, Inc.). Parametric data are expressed as the mean and standard deviation, while nonparametric data are expressed as the median and range. Student's t test and the Mann‒Whitney test were used to compare parameters between groups. One-way ANOVA with Dunnett's post hoc test was used to compare values within groups over time. A chi-square test was used to compare groups requiring rescue analgesia and vasopressors. P values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered to indicate statistical significance.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eTwenty dogs were enrolled and completed the study uneventfully.\u003c/p\u003e \u003cp\u003eThe mean weight and age did not differ between the groups: 30\u0026thinsp;\u0026plusmn;\u0026thinsp;12 kg (NaCl) and 32\u0026thinsp;\u0026plusmn;\u0026thinsp;13 kg (DEX), 6.3\u0026thinsp;\u0026plusmn;\u0026thinsp;2.5 years (NaCl) and 7.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.7 years (DEX).\u003c/p\u003e \u003cp\u003eIntraoperative administration of fentanyl was required in 5/10 dogs in the NaCl group and 0/10 dogs in the DEX group (p\u0026thinsp;=\u0026thinsp;0.03).\u003c/p\u003e \u003cp\u003eA significantly greater number of dogs in the NaCl group (8/10) required vasopressors (p\u0026thinsp;=\u0026thinsp;0.02) than did those in the DEX group (2/10). The heart rate was significantly lower in the DEX group than in the NaCl group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) throughout the entire treatment period (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). There were no significant differences in systolic or mean arterial pressure (SAP or MAP), F\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ee\u003c/span\u003e\u0026rsquo;Iso (Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), temperature, saturation of peripheral oxygen (SpO\u003csub\u003e2\u003c/sub\u003e), or PE\u0026rsquo;CO\u003csub\u003e2\u003c/sub\u003e between the groups.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe duration of postoperative analgesia was significantly longer (604\u0026thinsp;\u0026plusmn;\u0026thinsp;130 minutes) in the DEX group than in the NaCl group (400\u0026thinsp;\u0026plusmn;\u0026thinsp;81 minutes) (p\u0026thinsp;=\u0026thinsp;0.0005). All the dogs recovered uneventfully, with no complications noted during follow-up evaluation at 24 hours, 7 days, 14 days or 30 days after surgery.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study confirmed that the administration of a 1 mcg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e h\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e dexmedetomidine CRI in dogs undergoing TTA surgery prolongs the duration of postoperative analgesia and reduces the requirement for intraoperative analgesics and vasopressors.\u003c/p\u003e \u003cp\u003eThe mechanism through which dexmedetomidine enhances the efficacy of peripheral nerve blockade is uncertain and may differ if given intravenously or locally. Brummett and colleagues evaluated the activity of alpha-2-adrenergic agonists administered perineurally in combination with local anesthetics; they hypothesized that the synergistic effects of dexmedetomidine are likely due to the increased blockade of the hyperpolarization-activated cation current and not to agonism of the alfa-2-adrenoceptor. In that study, dexmedetomidine was administered locally (perineural), and the authors concluded that the effects were peripheral and not due to centrally mediated or systemic analgesia\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. It has also been proposed that dexmedetomidine-induced vasoconstriction may decrease the plasma absorption of locally administered anesthetic agents, subsequently leading to a prolonged and increased concentration of local anesthetic available to nerve fibers. This hypothesis is supported by the findings of a study in which the plasma concentration of bupivacaine administered intraperitoneally was similar between groups when the anesthetic was administered with either dexmedetomidine or adrenaline\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Another option is the supraspinal action of dexmedetomidine; the alpha-2 receptor binds to the locus coeruleus in the brainstem, decreases the release of norepinephrine, inhibits sympathetic activity and action at the dorsal horn, and alters the modulation of nociceptive signals\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOur study showed that a 1 mcg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e h\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e CRI of dexmedetomidine in dogs prolonged the duration of postoperative peripheral nerve blockade and delayed the need to administer postoperative opioids. This finding suggested that dexmedetomidine selectively prolongs sensory blockade over motor blockade, a finding that has also been suggested previously in human medicine\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. In veterinary medicine, a recent study revealed that an IV infusion of dexmedetomidine prolongs the duration of perineural lidocaine sensory blockade without impacting motor function\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Dexmedetomidine infusions have also been demonstrated to increase sensory blockade without significantly impairing motor function or causing bradycardia when given IV during bupivacaine-induced spinal anaesthesia\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Interestingly, that same study revealed that dexmedetomidine infusions increased the analgesic duration of bupivacaine-induced spinal anesthesia by approximately 50 minutes\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn our study, dogs that received a dexmedetomidine CRI did not require rescue analgesia during surgery, suggesting that the dose used, in combination with the nerve blocks, is helpful for covering intraoperative analgesia during TTA. In fact, it is possible that the dose of 1 mcg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e h\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e dexmedetomidine CRI fills any \u0026ldquo;analgesic holes\u0026rdquo; not covered by regional blockade, thus contributing to a multimodal analgesic approach. These findings are similar to those of Lovell and colleagues, who compared the analgesic efficacy of fentanyl alone to that of dexmedetomidine/ketamine infusion and suggested that the use of dexmedetomidine and ketamine might be a valid alternative for treating opioid-free aesthesia, as no significant differences in pain management were reported between the two groups\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. There are several reasons that may explain the reduced need for intraoperative analgesia in dogs receiving a dexmedetomidine CRI, which are widely discussed in human and veterinary medicine\u003csup\u003e\u003cspan additionalcitationids=\"CR25\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn our study, the DEX group had a lower heart rate (HR) and required significantly less vasopressor administration than did the NaCl group. The effects of dexmedetomidine on the cardiovascular system are well known, with bradycardia, increased peripheral resistance and decreased cardiac output being the most important. The reason why a lower DEX concentration is associated with a lower requirement for vasopressors is not fully understood, and several mechanisms have been proposed to explain how alpha-2 agonists improve vasopressor responsiveness. Pichot \u003cem\u003eet al\u003c/em\u003e suggested that dexmedetomidine can reduce the downregulation of alpha-1 receptors and/or produce gradual resensitization of alpha-1 adrenergic receptors by reducing the sympathetic outflow and release of endogenous catecholamines observed in patients with sepsis\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. It has also been proposed that α-2 agonists may act on vascular smooth muscle cells via local mechanisms, and the presynaptic action of α-2 agonists could, by reducing the release of endogenous noradrenaline, lead to the upregulation of postsynaptic α-1 receptors\u003csup\u003e\u003cspan additionalcitationids=\"CR29\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. Although the potential benefit of dexmedetomidine in decreasing vasopressor administration has been studied in several human clinical settings\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e its clinical effect on hemodynamic variables in veterinary patients is lacking. That said, the effects of the dexmedetomidine CRI found in the current study agree with the cardiovascular effects reported in two experimental studies in dogs undergoing anesthesia\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e,\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOur study has some limitations. The ideal CRI dosage of dexmedetomidine required to provide analgesia is not well known and varies within the veterinary literature. The most frequently reported doses range from 0.5 to 1 mcg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e h\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e and are administered alone or in combination with other drugs as a CRI\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e,\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. However, it has been suggested that a CRI dosage of 3 mcg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e h\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e is necessary in some cases to achieve an algesia effect in dogs and that 1 mcg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e h\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e CRI doses provide only a sedative effect\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. Finally, two operators with different levels of experience performed the peripheral nerve blocks, which may have introduced bias regarding the success and duration of peripheral nerve blockade. However, two operators were more reflective of clinical practice, as different clinicians are required to cover anesthesia shifts and subsequently perform nerve blocks.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe current study confirmed that a CRI of dexmedetomidine of 1 mcg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e h\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e can prolong the analgesic effects of peripheral nerve blockade in dogs by approximately 2 hours. Dexmedetomidine infusions can also reduce the intraoperative need for supplemental analgesia and vasopressor administration. Further studies using different dexmedetomidine CRIs and enrolling more patients are recommended.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCDF, AB: study design, data management, data interpretation, statistical analysis and preparation of manuscript.\u003c/p\u003e\n\u003cp\u003eEB, SP and EA: study design, data management, and preparation of manuscript.\u003c/p\u003e\n\u003cp\u003eSB: study design, data interpretation, preparation and revision of the manuscript.\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no external funding.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u0026nbsp;\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eCDF, AB: study design, data management, data interpretation, statistical analysis and preparation of manuscript.EB, SP and EA: study design, data management, and preparation of manuscript.SB: study design, data interpretation, preparation and revision of the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHelb, J.R. \u003cem\u003eet al.\u003c/em\u003e A preemptive multimodal pathway featuring peripheral nerve block improves perioperative outcomes after major orthopedic surgery. \u003cem\u003eReg. 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Efficacy and pharmacokinetics of bupivacaine with epinephrine or dexmedetomidine after intraperitoneal administration in cats undergoing ovariohysterectomy\u003cem\u003e. Can J Vet Res\u003c/em\u003e. 82:124-130 (2018).\u003c/li\u003e\n\u003cli\u003eAbdallah, F. W. \u003cem\u003eet al.\u003c/em\u003e IV and Perineural Dexmedetomidine Similarly, Prolong the Duration of Analgesia after Interscalene Brachial Plexus Block: A Randomized, Three-arm, Triple-masked, Placebo-controlled Trial. \u003cem\u003eAnesthesiology\u003c/em\u003e. 124:683\u0026ndash;695 (2016).\u003c/li\u003e\n\u003cli\u003eSarotti, D., Rabozzi, R., Franci, P. Effects of intravenous dexmedetomidine infusion on local anesthetic block: T A spinal anesthesia clinical model in dogs undergoing hind limb surgery. \u003cem\u003eRes Vet Sci\u003c/em\u003e. 124:93\u0026ndash;98 (2019).\u003c/li\u003e\n\u003cli\u003eLovell S. \u003cem\u003eet al.\u003c/em\u003e Randomized clinical trial comparing outcomes after fentanyl or ketamine-dexmedetomidine analgesia in thoracolumbar spinal surgery in dogs. \u003cem\u003eJ Vet Intern Med\u003c/em\u003e. 36:1742\u0026ndash;1751 (2022).\u003c/li\u003e\n\u003cli\u003eGrape, S., Kirkham, K.R., Frauenknecht, J., Albrecht, EIntra-operative analgesia with remifentanil vs. dexmedetomidine: a systematic review and meta-analysis with trial sequential analysis. \u003cem\u003eAnesthesia\u003c/em\u003e. 74:793-800 (2019).\u003c/li\u003e\n\u003cli\u003eDi Franco, C., Evangelista, F., Briganti, A. 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Cardiovascular effects of two dexmedetomidine doses: experimental study in dogs. \u003cem\u003eRev. Bras. Anestesiol\u003c/em\u003e. 53:784-796 (2003).\u003c/li\u003e\n\u003cli\u003eCongdon, J.M., Marquez, M., Niyom, S., Boscan, P. Cardiovascular, respiratory, electrolyte and acid‒base balance during continuous dexmedetomidine infusion in anesthetized dogs. \u003cem\u003eVet Anaesth Analg\u003c/em\u003e. 40:464-471 (2013).\u003c/li\u003e\n\u003cli\u003eOostrom, H., Doornenbal, A., Schot, A., Stienen, P.J., Hellebrekers, L.J. Neurophysiological assessment of the sedative and analgesic effects of a constant rate infusion of dexmedetomidine in the dog. \u003cem\u003eVet J\u003c/em\u003e. 190:338\u0026ndash;44. (2011)\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3925108/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3925108/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe aim of this study was to evaluate whether a continuous rate infusion (CRI) of dexmedetomidine could prolong the analgesic effect of peripheral nerve blocks. Twenty client-owned dogs were enrolled and randomly divided into 2 groups. The DEX group received dexmedetomidine infusion at 1 mcg kg\u003csup\u003e-1\u003c/sup\u003e h\u003csup\u003e-1\u003c/sup\u003e, and the NaCl group received an equivalent volume infusion of saline. Sciatic, saphenous and obturator nerve blocks were performed using 0.1 mL kg\u003csup\u003e-1\u003c/sup\u003e 0.5% ropivacaine/block. Intraoperative fentanyl was administered if the heart rate and/or mean arterial pressure (MAP) increased \u0026gt;15% from the previous measurement, and vasopressors were administered if the MAP was ≤ 70 mmHg. Postoperative pain was assessed every hour using the Glasgow Composite Pain Scale (GCPS). Postoperative rescue analgesia consisted of methadone (0.2 mg kg\u003csup\u003e-1\u003c/sup\u003e IV) and carprofen (2 mg kg\u003csup\u003e-1\u003c/sup\u003e IV). A greater number of dogs in the NaCl group required fentanyl (5/10 p= 0.03) and vasopressors (8/10, p=0.02) than did those in the DEX group (0/10 and 2/10, respectively). The duration of postoperative analgesia was significantly longer (604 ± 130 minutes) in the DEX group than in the NaCl group (400 ± 81 minutes, p=0.0005).\u003c/p\u003e\n\u003cp\u003eDexmedetomidine infusion at 1 mcg kg\u003csup\u003e-1\u003c/sup\u003e h\u003csup\u003e-1\u003c/sup\u003e reduces intraoperative analgesic and vasopressor requirements during orthopedic surgery and prolongs the postoperative analgesic effect of nerve blocks.\u003c/p\u003e","manuscriptTitle":"Effect of dexmedetomidine infusion on the analgesic duration of peripheral nerve blocks in dogs: a randomized clinical study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-22 21:26:03","doi":"10.21203/rs.3.rs-3925108/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-04-02T08:51:51+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-03-25T13:40:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"ad4423df-0cdd-4822-bc93-ac09ecab77e5","date":"2024-03-22T10:09:16+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-03-22T09:20:47+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-03-19T08:34:44+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-02-20T16:00:31+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-02-20T15:31:04+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-02-03T19:19:33+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"383a96c6-076a-443a-880a-877ee6eca907","owner":[],"postedDate":"February 22nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":28876168,"name":"Health sciences/Health care"},{"id":28876169,"name":"Health sciences/Medical research"},{"id":28876170,"name":"Health sciences/Medical research/Study design/Randomized controlled trials"}],"tags":[],"updatedAt":"2024-08-01T17:09:16+00:00","versionOfRecord":{"articleIdentity":"rs-3925108","link":"https://doi.org/10.1038/s41598-024-67894-x","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2024-07-24 16:15:53","publishedOnDateReadable":"July 24th, 2024"},"versionCreatedAt":"2024-02-22 21:26:03","video":"","vorDoi":"10.1038/s41598-024-67894-x","vorDoiUrl":"https://doi.org/10.1038/s41598-024-67894-x","workflowStages":[]},"version":"v1","identity":"rs-3925108","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3925108","identity":"rs-3925108","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}