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Comparison of the sedative effects of intranasal or intramuscular dexmedetomidine at low doses in healthy dogs: a randomized clinical trial

Published:August 11, 2022DOI:https://doi.org/10.1016/j.vaa.2022.08.003

      Abstract

      Objective

      To compare the sedative effects of dexmedetomidine administered either intranasally or intramuscularly to healthy dogs.

      Study design

      Prospective, randomized, blinded, clinical trial.

      Animals

      A group of 16 client-owned healthy dogs.

      Methods

      Dogs were randomly allocated to one of two groups that were administered dexmedetomidine 5 μg kg–1 via either the intranasal route (INDex), through a mucosal atomization device in one nostril, or the intramuscular route (IMDex), into the epaxial muscles. Ease of intranasal administration, sedation score, onset of sedation, cardiopulmonary variables, mechanical nociceptive thresholds (MNTs) and response to venous catheterization were recorded at 0 (baseline), 5, 10, 15, 20, 25, 30, 35, 40 and 45 minutes, following drug administration. Data were compared with the one-way anova, Mann-Whitney U test, and chi-square test, where appropriate.

      Results

      Groups were not different for age, sex, weight, body condition score or temperament. Sedation scores, MNTs and response to intravenous catheter placement were not different when dexmedetomidine was administered by either route (p = 0.691; p = 0.630 and p = 0.435, respectively). Onset of sedation was not different between groups INDex and IMDex reaching a score of 4.2 ± 0.9 and 5.5 ± 1.2 at 9 ± 5 and 8 ± 4 minutes, respectively (p = 0.467). The highest sedation score was achieved at 30 and 35 minutes and sedation scores were 9.7 ± 2.0 and 9.5 ± 2.3 in groups INDex and IMDex, respectively (p = 0.799). Respiratory rate was higher in group INDex (p = 0.014), while there were no differences between routes in heart rate (p = 0.275), systolic (p = 0.957), diastolic (p = 0.837) or mean arterial pressure (p = 0.921).

      Conclusions and clinical relevance

      Intranasal administration of dexmedetomidine at 5 μg kg–1 provides effective sedation in healthy dogs.

      Keywords

      Introduction

      Sedation is commonly required to facilitate handling during the perioperative period in companion animal practice. Sedative drugs can be administered via different routes, the most common being intramuscular (IM) and intravenous (IV). However, intranasal (IN) administration of sedative drugs may represent an alternative route (
      • Jafarbeglou M.
      • Marjani M.
      Comparison of the sedative effects of medetomidine administered intranasally, by atomization or drops, and intramuscular injection in dogs.
      ).
      The physiological features of the nasal cavity make it a suitable target for drug delivery. In dogs with an average weight of 10 kg, the nasal cavity has a volume of 20 mL with a surface area of 221 cm2 (
      • Schreider J.P.
      Nasal airway anatomy and inhalation deposition in experimental animals and people.
      ). Furthermore, the extensive vascularization of the nasal mucosa provides an optimal absorption surface for drug delivery (
      • Erdö F.
      • Bors L.A.
      • Farkas D.
      • et al.
      Evaluation of intranasal delivery route of drug administration for brain targeting.
      ). Blood flow to the upper respiratory tract mucosa is extensive and considered to be greater per cm3 of tissue than in the brain, liver or muscle (
      • Dale O.
      • Hjortkjaer R.
      • Kharasch E.D.
      Nasal administration of opioids for pain management in adults.
      ), thus providing an optimal absorption surface and increased drug bioavailability compared with other tissues. It also offers the possibility to achieve a sedative effect by IN drug administration via nasal-to-brain delivery. It provides a direct route to the brain without the need to penetrate the blood–brain barrier, and potentially avoids the adverse events that would occur when drugs are systemically absorbed. In humans, IN administration of dexmedetomidine may avoid acute haemodynamic changes (
      • Yoo H.
      • Iirola T.
      • Vilo S.
      • et al.
      Mechanism-based population pharmacokinetic and pharmacodynamic modeling of intravenous and intranasal dexmedetomidine in healthy subjects.
      ). The exact mechanism by which compounds transfer from the nasal mucosa to the brain is not fully understood yet. IN administration of drugs have been shown to enter the central nervous system via direct nose-to-brain transport along the olfactory nerve and the trigeminal nerve (
      • Martins P.P.
      • Smyth H.D.C.
      • Cui Z.
      Strategies to facilitate or block nose-to-brain drug delivery.
      ;
      • Wang Z.
      • Xiong G.
      • Tsang W.C.
      • et al.
      Nose-to brain delivery.
      ). The main limitation of the administration of drugs by IN route is the partial loss of the drug dose when sneezing occurs after its application, or when the drug flows downstream and is swallowed, reducing the bioavailability as it passes through the gastrointestinal system.
      Not all drugs are adequately absorbed by the IN route, and the efficacy is determined by their physicochemical properties. Drugs with a low molecular weight, less than 300 Da, have a rapid absorption by the IN route, whereas absorption of drugs with a molecular weight 300–1000 Da relies on the drug’s liposolubility. Dexmedetomidine, is an α2-adrenoreceptor agonist (alpha-2) lipophilic drug with a low molecular weight (237 Da) and may be considered a suitable drug for IN administration (
      • Micieli F.
      • Santangelo B.
      • Reynaud F.
      • et al.
      Sedative and cardiovascular effects of intranasal or intramuscular dexmedetomidine in healthy dogs.
      ). The IN administration of an alpha-2 is increasingly employed for the sedation and restraint of human paediatric patients. It is considered an effective route and it is not associated with unpleasant sensations, especially in non-collaborative children (
      • Kim H.J.
      • Shin W.J.
      • Park S.
      • et al.
      The sedative effects of the intranasal administration of dexmedetomidine in children undergoing surgeries compared to other sedation methods: A systematic review and meta-analysis.
      ;
      • Tervonen M.
      • Pokka T.
      • Kallio M.
      • Peltoniemi O.
      Systematic review and meta-analysis found that intranasal dexmedetomidine was a safe and effective sedative drug during paediatric procedural sedation.
      ). The IN route has been reported in dogs (
      • Micieli F.
      • Santangelo B.
      • Reynaud F.
      • et al.
      Sedative and cardiovascular effects of intranasal or intramuscular dexmedetomidine in healthy dogs.
      ;
      • Jafarbeglou M.
      • Marjani M.
      Comparison of the sedative effects of medetomidine administered intranasally, by atomization or drops, and intramuscular injection in dogs.
      ;
      • Santangelo B.
      • Harel M.
      • Fourel I.
      • et al.
      Intranasal dexmedetomidine in healthy beagles: An echocardiographic and pharmacokinetic/pharmacodynamic study.
      ), rabbits (
      • Weiland L.
      • Kluge K.
      • Kutter A.P.N.
      • Kronen P.W.
      Clinical evaluation of intranasal medetomidine-ketamine and medetomidine-S(+)-ketamine for induction of anaesthesia in rabbits in two centres with two different administration techniques.
      ), birds (
      • Hornak S.
      • Liptak T.
      • Ledecky V.
      A preliminary trial of the sedation induced by intranasal administration of midazolam alone or in combination with dexmedetomidine and reversal by atipamezole for a short-term immobilization in pigeons.
      ) and turtles (
      • Schnellbacher R.W.
      • Hernandez S.M.
      • Tuberville T.D.
      • et al.
      The efficacy of intranasal administration of dexmedetomidine and ketamine to Yellow-Bellied Sliders (Trachemys scripta scripta).
      ). Advantages of the IN route may include improvement of the animal’s tolerance to drug administration with no pain and reduced anxiety compared with the IM route, and not requiring trained personnel (
      • Charalambous M.
      • Volk H.A.
      • Van Ham L.
      • Bhatti S.F.
      First-line management of canine status epilepticus at home and in hospital-opportunities and limitations of the various administration routes of benzodiazepines.
      ).
      Dexmedetomidine and medetomidine produce sedation when administered IN in dogs, although relatively high doses were employed (20 and 40 μg kg–1, respectively) (
      • Micieli F.
      • Santangelo B.
      • Reynaud F.
      • et al.
      Sedative and cardiovascular effects of intranasal or intramuscular dexmedetomidine in healthy dogs.
      ;
      • Jafarbeglou M.
      • Marjani M.
      Comparison of the sedative effects of medetomidine administered intranasally, by atomization or drops, and intramuscular injection in dogs.
      ;
      • Santangelo B.
      • Harel M.
      • Fourel I.
      • et al.
      Intranasal dexmedetomidine in healthy beagles: An echocardiographic and pharmacokinetic/pharmacodynamic study.
      ). Since the effects of alpha-2 agonist drugs are dose related (
      • Sinclair M.D.
      A review of the physiological effects of α2-agonists related to the clinical use of medetomidine in small animal practice.
      ), higher doses of dexmedetomidine provide more reliable and profound sedation, but lower doses are commonly employed in clinical practice (dexmedetomidine 1–10 μg kg–1) (
      • Murrell J.C.
      Pre-anaesthetic medication and sedation.
      ).
      The aim of this study was to compare the sedative effects of 5 μg kg–1 of dexmedetomidine administered via either the IN (INDex) or the IM (IMDex) routes to healthy dogs. We hypothesized that the IN route would provide a degree of sedation not dissimilar to that produced by the IM route.

      Materials and methods

      The study was approved by the institutional ethics committee (Complutense University of Madrid, reference number 03/2020). Informed owner consent was obtained in all cases.

      Animals

      A group of 16 client-owned dogs scheduled for elective procedures were enrolled in the study. Dogs were considered healthy [American Society of Anesthesiologists (ASA) physical status I or II] based on medical history, physical examination, electrocardiography, and clinical laboratory data: complete blood count and serum biochemical analysis. Exclusion criteria included brachycephalic dogs, aggressive dogs or dogs weighing < 5 kg, aged < 6 months, ASA physical status classification > II, or history of respiratory or cardiac disease and owner’s refusal.

      Study design

      A prospective, randomized, blinded, clinical trial was designed. The dogs were fasted for 12 hours, and water was available until 1 hour prior to beginning the study. Before starting the experiment, dogs were placed in a quiet room for 10 minutes to allow acclimatization to the environment and to the researchers. The study timeline shows the flow of events during the study (Fig. 1). Prior to sedation, temperament was assessed using a score: 1, calm friendly dog; 2, mildly excited and/or nervous; 3, moderately excited and/or nervous; and 4, very excited or nervous (
      • Maddern K.
      • Adams V.J.
      • Hill N.A.
      • Leece E.A.
      Alfaxalone induction dose following administration of medetomidine and butorphanol in the dog.
      ). Body condition score (BCS) was assessed using a 1–9 scale (highest score corresponded to obese animals) (
      • Laflamme D.
      Development and validation of a body condition score system for dogs.
      ), and body weight was recorded.
      Figure 1
      Figure 1Study timeline. Following baseline data recording, dexmedetomidine was administered via either the intranasal (IN) or intramuscular (IM) route to 16 healthy dogs (n = 8 per group) 20 minutes before intravenous (IV) catheterization. Recorded data at 5 minute intervals were, in order, heart rate (HR), respiratory frequency (fR), noninvasive arterial blood pressure systolic, diastolic and mean (SAP/DAP/MAP), sedation score (SS) and mechanical nociceptive thresholds (MNTs).
      Dogs were randomly allocated to one of two groups, using a computer-generated randomization list (www.randomisation.com) to be administered dexmedetomidine (5 μg kg–1; Sedadex 0.5 mg mL–1; Dechra, Spain) either IM (n = 8) or IN (n = 8). For blinding purposes, one investigator prepared two syringes, one with dexmedetomidine and another with the equivalent volume of saline, labelled IM or IN, while another investigator performed all assessments (ease of administration, sedation, pain assessment and physiological variables).
      In group INDex, dogs were administered dexmedetomidine using the Mucosal Atomization Device (MAD Nasal 300; Teleflex Medical Iberia SA, Spain). In all cases, the administered dose of dexmedetomidine was increased taking into consideration the dead space of the atomization device (0.06 mL according to manufacturer’s user guide). The drug was administered into one nostril while the dog’s head was elevated at 30–40 ° for 1 minute after the drug administration. In group IMDex the drug was administered by injecting with a 23 gauge, 25 mm needle (Sterican; BBraun, Spain) into the epaxial muscles (longissimus dorsi).
      To evaluate the ease of IN administration, a five-point scale was used: +2, the easiest administration (dog offers no physical resistance); +1, easy to do (dog minimally physically resistant); 0, able to do with modest effort (dog may be somewhat physically resistant); –1, difficult to do (dog very physically resistant); and –2, the IN administration was impossible as the dog would have required excessive physical restraint (
      • Hopfensperger M.J.
      • Messenger K.M.
      • Papich M.G.
      • Sherman B.L.
      The use of oral transmucosal detomidine hydrochloride gel to facilitate handling in dogs.
      ).

      Cardiopulmonary variables

      Heart rate (HR) was recorded using a multiparametric monitor (iMEC 8Vet; Mindray Medical International, Guangdong, China) with electrode patches taped on the digital pads of the thoracic limbs and left pelvic limb. Respiratory frequency (fR) was recorded by observation of chest wall excursions for 1 minute. A blood pressure cuff (40% of the limb circumference) was placed above the right tarsus (Rad-97; Massimo, CA, USA) to measure noninvasive systolic (SAP), diastolic (DAP), and mean arterial blood pressure (MAP). All cardiopulmonary variables were recorded before and every 5 minutes until 45 minutes after drug administration.

      Sedation

      Sedation scores (SS) were assessed by an experienced observer using a numerical descriptive scale ranging from 0 (lack of sedation) to 15 (maximum sedation). The scoring system evaluated spontaneous posture, palpebral reflex, eye position, response to sound (handclap), resistance to lateral recumbency positioning and overall sedation appearance (
      • Gurney M.
      • Cripps P.
      • Mosing M.
      Subcutaneous pre-anaesthetic medication with acepromazine buprenorphine is effective as and less painful than the intramuscular route.
      ). Onset of sedation was defined as the time in minutes until the presence of muscle relaxation of the animal and spontaneous recumbency (either sternal or lateral) after drug administration.

      Mechanical nociceptive thresholds

      Animals were also assessed to determine mechanical nociceptive thresholds (MNTs) using a handheld algometer (Prod Pro algometer; Topcat Metrology, UK). Nociceptive stimuli were applied at each time point immediately after sedation was scored and cardiopulmonary variables had been recorded. The device recorded the maximum force applied perpendicularly to the skin over the left carpus. Pressure was increased until any of the following reactions were noted: withdrawal of the thoracic limb, attempt to bite or vocalization. The device then displayed the highest reading reached. For each time point MNTs, were assessed in triplicates, with 1 minute interval between each measurement and the average score was calculated and recorded. A control group to assess change in MNTs over time was not included. The device was zeroed before each measurement. The load cell measurement range was 0–25 N and the device’s tip had a 4 mm diameter. All measurements were recorded before drug administration (T0, baseline) and at 5, 10, 15, 20, 25, 30, 35, 40 and 45 minutes afterwards.

      Response to catheterization

      An IV catheter was placed in the cephalic vein 20 minutes after dexmedetomidine administration. Response to catheterization was assessed using a score ranging from 0 (no response) to 2 (obvious vocalization or withdrawal of the limb) (
      • Valverde A.
      • Cantwell S.
      • Hernandez J.
      • Brotherson C.
      Effects of acepromazine on the incidence of vomiting associated with opioid administration in dogs.
      ).

      Statistical analysis

      A power analysis was used to estimate the minimum sample size required in each group with an 80% power and a significance level of 5% to detect a difference of 3 points out of 15 in the sedation score between groups with a standard deviation (SD) of 2.8 (
      • Arenillas M.
      • Aguado D.
      • Canfrán S.
      • et al.
      Sedative effects of two doses of alfaxalone in combination with methadone and a low dose of dexmedetomidine in healthy Beagles.
      ), which gave a sample size of 14 dogs per group. However, recalculation of the sample size from the ongoing results, with an actual SD of 2.1 at 30 minutes, when the degree of sedation was strongest, suggested a final sample size of eight dogs per group.
      Data were tested for normality using the Shapiro-Wilk test. Mean ± SD for the normally distributed variables (SS, MNT, onset of sedation, high sedation score, HR, SAP, DAP, MAP), and median (range) for non-normally distributed variables (fR, BCS, temperament, response to IN administration, response to catheterization) were used. Normally distributed data for repeated measures was analysed with repeated measures anova (General Linear Model), while non-repeated measures or measures at each time point were compared between groups using with the t test, or Mann–Whitney U test for non-normally distributed data. Chi-square test was used to compare BCS, sex, temperament, catheterization and administration response between groups. A p value of < 0.05 was considered statistically significant. Data analysis was performed using SPPS version 25; IBM Corp., NY, USA).

      Results

      A total of 29 healthy dogs were enrolled in the study. Of these dogs, a total of 13 dogs were excluded: in six animals, the owner refused to participate in the study and four dogs were excluded owing to their fractious nature. In another three dogs, the MNT reached the threshold cut-off value (>15 N) with no obvious signs of pain during basal measurements. Finally, 16 dogs scheduled for elective procedures (gonadectomy n = 8; dental cleaning procedures n = 4; excision of cutaneous tumours n = 4) were included in the analysis(groups INDex and IMDex, n = 8 each; Fig. 2). All included dogs completed the observation period without complications.
      Figure 2
      Figure 2Consolidated Standards of Reporting Trials (Consort) flow diagram showing details of the animals enrolled in the study.
      There were no significant differences between groups INDex and IMDex in terms of sex distribution (female:male; 3:5 and 5:3), age (5.6 ± 3.9 and 6.4 ± 4 years), body weight (24.6 ± 4.0 and 20.2 ± 4.2 kg), BCS [5 (5–5) and 5 (4–6)] or temperament [2 (1–4) and 2(1–4)].
      No adverse effects were observed after the IN or IM administration of dexmedetomidine. All dogs tolerated the IN administration well, which was scored as easy or very easy to perform [group INDex 2 (1–2); group IMDex 1.5 (–1–2)] (p = 0.207). Three dogs in group IMDex and two dogs in group INDex sneezed after IN administration of saline and dexmedetomidine, respectively, and two dogs in group INDex swallowed after drug administration. There were no differences in the occurrence of sneezing (p = 0.317) or swallowing (p = 0.131) between groups.

      Sedation

      No significant differences were found when dexmedetomidine was administered via either the IN or IM routes (p = 0.691; Fig. 3). Onset of sedation did not differ between groups INDex and IMDex reaching a score of 4.2 ± 0.9 and 5.5 ± 1.2 at 9 ± 5 and 8 ± 4 minutes, respectively (p = 0.467). The highest sedation score was achieved at 30 minutes in group INDex and at 35 minutes in group IMDex (SS: 9.7 ± 0.7 and 9.5 ± 0.8, respectively; p = 0.799).
      Figure 3
      Figure 3Sedation scores from 16 healthy dogs sedated with dexmedetomidine via either the intranasal (IN) or intramuscular (IM) routes (n = 8 per group). Data are expressed as mean ± standard deviation.

      Physiological variables

      Data from physiological variables are shown in Table 1. The fR was higher in group INDex than in group IMDex (averaged value: 34 and 20 breaths minute–1, respectively; p = 0.014), while there were no differences between groups for the number of dogs panting (p = 0.302).
      Table 1Values of sedation score, heart rate (HR), noninvasive systolic, diastolic and mean arterial blood pressure, respiratory frequency (fR) and mechanical nociceptive thresholds (MNTs), from 16 healthy dogs before (T0: baseline) and during the 45 minutes following administration of dexmedetomidine (5 μg kg–1) via either the intranasal (IN; n = 8) or intramuscular (IM; n = 8) route. Data are expressed as mean ± standard deviation or median (range) as appropriate
      Time (minutes)
      VariableRouteBaseline51015202530354045
      Heart rate (beats minute–1)IM123 ± 1687 ± 2475 ± 2867 ± 3064 ± 2761 ± 2560 ± 2355 ± 2153 ± 2256 ± 24
      IN121 ± 22110 ± 2696 ± 3082 ± 2175 ± 1980 ± 1563 ± 1762 ± 2365 ± 2162 ± 21
      Respiratory rate
      Significant difference between groups (p < 0.05).
      (breaths minute–1)
      IM24 (16–41)32 (12–41)30 (12–41)20 (9–36)20 (12–24)16 (8–24)18 (8–36)16 (8–24)12 (12–24)12 (8–36)
      IN41 (16–41)41 (20–41)41 (16–41)40 (12–41)38 (12–41)32 (12–41)22 (12–41)24 (12–41)32 (12–41)32 (12–41)
      Systolic arterial pressure (mmHg)IM133 ± 24139 ± 27132 ± 24145 ± 27141 ± 21139 ± 29141 ± 18128 ± 19138 ± 15138 ± 13
      IN138 ± 19136 ± 32135 ± 21139 ± 31142 ± 22139 ± 18139 ± 21129 ± 11134 ± 20139 ± 23
      Diastolic arterial pressure (mmHg)IM88 ± 2091 ± 1683 ± 2092 ± 2593 ± 1487 ± 2787 ± 2384 ± 1686 ± 1390 ± 17
      IN101 ± 1689 ± 2591 ± 2395 ± 2493 ± 1686 ± 1387 ± 1184 ± 1182 ± 2183 ± 17
      Mean arterial pressure (mmHg)IM105 ± 19107 ± 1999 ± 20110 ± 25109 ± 14105 ± 26105 ± 2098 ± 15103 ± 12105 ± 13
      IN113 ± 16105 ± 26106 ± 21109 ± 26109 ± 16104 ± 12105 ± 1499 ± 999 ± 19101 ± 15
      Mechanical nociceptive thresholds (N)IM4.4 ± 0.66.3 ± 3.77.3 ± 3.38.7 ± 4.28.8 ± 3.89.6 ± 3.69.5 ± 3.89.7 ± 1.210.1 ± 3.49.7 ± 3.8
      IN4.7 ± 1.55.7 ± 2.26.4 ± 2.47.4 ± 3.58.6 ± 3.39.8 ± 4.19.7 ± 4.28.7 ± 4.37.6 ± 4.27.2 ± 3.9
      Sedation scoreIM0.0 ± 0.02.5 ± 0.75.5 ± 1.27.2 ± 0.78.0 ± 0.89.0 ± 1.19.3 ± 1.09.5 ± 0.89.3 ± 0.99.2 ± 0.9
      IN0.2 ± 0.11.8 ± 0.54.2 ± 0.96.6 ± 0.88.2 ± 0.88.8 ± 0.69.7 ± 0.78.8 ± 0.79.7 ± 0.88.5 ± 0.7
      Significant difference between groups (p < 0.05).
      No differences were found between groups in HR (p = 0.275), SAP (p = 0.957), DAP (p = 0.837) and MAP (p = 0.921). The maximum decrease in HR from baseline values did not differ between groups: 58 ± 17% at 36 ± 6 minutes and 52 ± 12% at 34 ± 9 minutes in groups IMDex and INDex, respectively (p = 0.373). The maximum increase of MAP was not different between groups: 22 ± 33% at 19 ± 15 minutes, and 15 ± 15% at 16 ± 12 minutes in groups IMDex and INDex, respectively (p = 0.115).

      Intravenous catheterization

      There were no differences between groups INDex and IMDex regarding the response to IV catheter placement in the cephalic vein 20 minutes after dexmedetomidine administration, where most dogs did not respond [0 (0–1) and 0 (0–2), respectively; p = 0.435)].

      Mechanical nociceptive thresholds

      Baseline MNTs were 4.7 ± 1.5 and 4.4 ± 0.6 N in groups INDex and IMDex, respectively. Peak MNT increases were 9.8 ± 4.1 N (128 ± 90%, minute 25) and 10.1 ± 3.4 N (149 ± 53%, minute 40) in groups INDex and IMDex, respectively. No differences were determined between groups for MNT values (p = 0.630; Table 1).

      Discussion

      Dexmedetomidine administered IN at relatively low doses of 5 μg kg–1 produced a degree of sedation that did not differ from that produced when administered IM to healthy dogs. Sedation was observed in all dogs after treatment regardless of the route of administration and most dogs did not respond to IV catheterization. Previous studies reported the effectiveness of the IN route although at the higher dose of dexmedetomidine (20 μg kg–1), which is less commonly employed before anaesthesia (
      • Santangelo B.
      • Harel M.
      • Fourel I.
      • et al.
      Intranasal dexmedetomidine in healthy beagles: An echocardiographic and pharmacokinetic/pharmacodynamic study.
      ). Furthermore, a higher degree of sedation was reported when high doses of dexmedetomidine (20 μg kg–1) were administered IN (
      • Micieli F.
      • Santangelo B.
      • Reynaud F.
      • et al.
      Sedative and cardiovascular effects of intranasal or intramuscular dexmedetomidine in healthy dogs.
      ) compared with the IM route. Such an effect could not be demonstrated in our study and may be related to the lower dose we used.
      The degree of sedation produced by the low dexmedetomidine dose we used was considered suitable for anaesthetic induction. However, the degree of sedation we observed was probably less than that produced by a higher dose of 20 μg kg–1 (
      • Micieli F.
      • Santangelo B.
      • Reynaud F.
      • et al.
      Sedative and cardiovascular effects of intranasal or intramuscular dexmedetomidine in healthy dogs.
      ;
      • Santangelo B.
      • Harel M.
      • Fourel I.
      • et al.
      Intranasal dexmedetomidine in healthy beagles: An echocardiographic and pharmacokinetic/pharmacodynamic study.
      ).
      Anyway, comparison of studies should be done carefully as several factors may affect the results. Sedation scales used in previous studies (Micieli et al. in 2017;
      • Santangelo B.
      • Harel M.
      • Fourel I.
      • et al.
      Intranasal dexmedetomidine in healthy beagles: An echocardiographic and pharmacokinetic/pharmacodynamic study.
      ) as well as in our study have not been validated. The sedation scale used in the present study is slightly different to that described in previous studies (Micieli et al. in 2017;
      • Santangelo B.
      • Harel M.
      • Fourel I.
      • et al.
      Intranasal dexmedetomidine in healthy beagles: An echocardiographic and pharmacokinetic/pharmacodynamic study.
      ). In addition to the differences in the sedation scale scores, subjective interpretation of the degree of sedation can affect the results. Other potential factors may involve the IM drug’s absorption which may be affected by the muscle groups used (
      • Carter J.E.
      • Lewis C.
      • Beths T.
      Onset and quality of sedation after intramuscular administration of dexmedetomidine and hydromorphone in various muscle groups in dogs.
      ), either the longissimus dorsi muscle (present study) (
      • Santangelo B.
      • Harel M.
      • Fourel I.
      • et al.
      Intranasal dexmedetomidine in healthy beagles: An echocardiographic and pharmacokinetic/pharmacodynamic study.
      ), or the rectus femoris muscle (
      • Micieli F.
      • Santangelo B.
      • Reynaud F.
      • et al.
      Sedative and cardiovascular effects of intranasal or intramuscular dexmedetomidine in healthy dogs.
      ). Also, handling the animals may affect the results, although we placed dogs in a quiet room to allow acclimatization to the environment and to the researcher as done by
      • Micieli F.
      • Santangelo B.
      • Reynaud F.
      • et al.
      Sedative and cardiovascular effects of intranasal or intramuscular dexmedetomidine in healthy dogs.
      . Indeed, dogs were studied in a quiet room alone, other than the presence of the experimenter who performed the data collection. Besides, the study was performed early in the morning, with low clinical activity thus reducing potentially stressful factors. In our study we also evaluated the MNTs, meaning we applied a nociceptive stimulus in triplicate at each time point (not used in previous studies) (
      • Micieli F.
      • Santangelo B.
      • Reynaud F.
      • et al.
      Sedative and cardiovascular effects of intranasal or intramuscular dexmedetomidine in healthy dogs.
      ), which could also have influenced the degree of sedation. However, the MNT testing device was applied after the degree of sedation was assessed. Also at 20 minutes, during the observation period, an IV catheter was placed. This stimulus was not performed in previous studies (
      • Micieli F.
      • Santangelo B.
      • Reynaud F.
      • et al.
      Sedative and cardiovascular effects of intranasal or intramuscular dexmedetomidine in healthy dogs.
      ).
      Despite all these differences, we found a moderate grade of sedation when we used a lower dose of dexmedetomidine (5 μg kg–1) from previous studies when higher (20 μg kg–1) doses were used (
      • Micieli F.
      • Santangelo B.
      • Reynaud F.
      • et al.
      Sedative and cardiovascular effects of intranasal or intramuscular dexmedetomidine in healthy dogs.
      ;
      • Santangelo B.
      • Harel M.
      • Fourel I.
      • et al.
      Intranasal dexmedetomidine in healthy beagles: An echocardiographic and pharmacokinetic/pharmacodynamic study.
      ).
      Onset of sedation was similar with both administration routes (9 ± 5 and 8 ± 4 minutes in IN or IM groups) as previously reported with higher doses of alpha-2 administered [6.3 ± 2.0 and 7.2 ± 2.5 minutes IN or IM groups, (
      • Jafarbeglou M.
      • Marjani M.
      Comparison of the sedative effects of medetomidine administered intranasally, by atomization or drops, and intramuscular injection in dogs.
      ); 6.3 ± 3.3 and 9.4 ± 4.6 minutes IN or IM groups, (
      • Micieli F.
      • Santangelo B.
      • Reynaud F.
      • et al.
      Sedative and cardiovascular effects of intranasal or intramuscular dexmedetomidine in healthy dogs.
      ); 21 ± 05 and 23 ± 12 minutes IN or IM groups, (
      • Santangelo B.
      • Harel M.
      • Fourel I.
      • et al.
      Intranasal dexmedetomidine in healthy beagles: An echocardiographic and pharmacokinetic/pharmacodynamic study.
      )].
      Peak SS in our study were similar following either the IN or IM routes and achieved by 30 and 35 minutes, respectively. These times were more rapid when compared with the IN use of 40 μg kg–1 of medetomidine (45 minutes) (
      • Jafarbeglou M.
      • Marjani M.
      Comparison of the sedative effects of medetomidine administered intranasally, by atomization or drops, and intramuscular injection in dogs.
      ) and similar compared with the IN administration of 20 μg kg–1 of dexmedetomidine (
      • Micieli F.
      • Santangelo B.
      • Reynaud F.
      • et al.
      Sedative and cardiovascular effects of intranasal or intramuscular dexmedetomidine in healthy dogs.
      ;
      • Santangelo B.
      • Harel M.
      • Fourel I.
      • et al.
      Intranasal dexmedetomidine in healthy beagles: An echocardiographic and pharmacokinetic/pharmacodynamic study.
      ) (23.5 ± 4.7 and 40 minutes, respectively).
      The optimal dose of dexmedetomidine administered IN in human medicine is approximately 2 μg kg–1 (
      • Lewis J.
      • Bailey C.R.
      Intranasal dexmedetomidine for sedation in children; a review.
      ). Allometric scaling is an empirical approach where the exchange of drug dose is based on normalization of the dose to body surface area. This method is frequently used in research for experimental purposes to predict an approximate dose based on data derived from other species. To convert canine doses in mg kg–1 to human equivalent doses (HEDs) in mg kg–1, the animal dose is multiplied by 0.54 (
      FDA
      Guidance for industry: Estimating the maximum safe starting dose in adult health volunteer.
      ). In our study, 5 μg kg–1 of dexmedetomidine in HED is 2.7 μg kg–1.
      In veterinary medicine, the optimal dose regimen of dexmedetomidine IN in dogs is unknown but may be close to 5 μg kg–1 as suggested from the present and previous studies (
      • Micieli F.
      • Santangelo B.
      • Reynaud F.
      • et al.
      Sedative and cardiovascular effects of intranasal or intramuscular dexmedetomidine in healthy dogs.
      ;
      • Santangelo B.
      • Harel M.
      • Fourel I.
      • et al.
      Intranasal dexmedetomidine in healthy beagles: An echocardiographic and pharmacokinetic/pharmacodynamic study.
      ). In the earlier studies, an increase in the dose did not produce a different degree of sedation. It is also true that with higher doses a deeper level of sedation is achieved, but with lower doses a moderate degree of sedation is achieved, sufficient for handling the animal during the preoperative period. However, further studies are needed to compare different doses of dexmedetomidine administered via the IN route in dogs.
      In the present study, dexmedetomidine IN was administered in one nostril as previously reported (
      • Jafarbeglou M.
      • Marjani M.
      Comparison of the sedative effects of medetomidine administered intranasally, by atomization or drops, and intramuscular injection in dogs.
      ) in contrast to other studies where both nostrils were simultaneously considered (
      • Micieli F.
      • Santangelo B.
      • Reynaud F.
      • et al.
      Sedative and cardiovascular effects of intranasal or intramuscular dexmedetomidine in healthy dogs.
      ;
      • Santangelo B.
      • Harel M.
      • Fourel I.
      • et al.
      Intranasal dexmedetomidine in healthy beagles: An echocardiographic and pharmacokinetic/pharmacodynamic study.
      ). We also employed lower doses allowing smaller volumes to be administered readily via one nostril with the drug being rapidly absorbed (
      • Wu H.
      • Hu K.
      • Jiang X.
      From nose to brain: understanding transport capacity and transport rate of drugs.
      ). The nasal mucosa’s low surface area limits the administration of active principles to low volumes (25–200 μL) (
      • Wu H.
      • Hu K.
      • Jiang X.
      From nose to brain: understanding transport capacity and transport rate of drugs.
      ), to avoid direct loss of the drug via rostral or caudal run-off. In children, the recommended optimal IN volume should not exceed 0.15–0.2 mL per nostril (
      • Mondardini M.C.
      • Amigoni A.
      • Cortellazzi P.
      • et al.
      Intranasal dexmedetomidine in pediatrics: update of current knowledge.
      ). A low dose of dexmedetomidine (5 μg kg–1) equates to a total volume to be administered of 0.01 mL kg–1. Therefore, the split administration of this volume into two nostrils would be 0.005 mL kg–1, which may be too low to adequately reach the olfactory epithelium where the drug must be absorbed. Previous reports have administered 0.02 mL kg–1 per nostril (
      • Micieli F.
      • Santangelo B.
      • Reynaud F.
      • et al.
      Sedative and cardiovascular effects of intranasal or intramuscular dexmedetomidine in healthy dogs.
      ;
      • Santangelo B.
      • Harel M.
      • Fourel I.
      • et al.
      Intranasal dexmedetomidine in healthy beagles: An echocardiographic and pharmacokinetic/pharmacodynamic study.
      ). Also, in the study published by
      • Jafarbeglou M.
      • Marjani M.
      Comparison of the sedative effects of medetomidine administered intranasally, by atomization or drops, and intramuscular injection in dogs.
      , it was considered less stressful to administer the drug into one rather than into both nostrils.
      In the present study, common side effects of alpha-2 drugs such as decreased HR or increased arterial blood pressure were similar when administered via either the IN or IM routes. We found a maximal HR reduction of approximately 50% by either route. Such a reduction is commonly observed following dexmedetomidine administered IM to dogs (
      • Granholm M.
      • McKusick B.C.
      • Westerholm F.C.
      • Aspegrén J.C.
      Evaluation of the clinical efficacy and safety of intramuscular and intravenous doses of dexmedetomidine and medetomidine in dogs and their reversal with atipamezole.
      ). Also, similar MAP increases of 15–22% were observed with both routes, also reported when higher doses of medetomidine were employed (
      • Jafarbeglou M.
      • Marjani M.
      Comparison of the sedative effects of medetomidine administered intranasally, by atomization or drops, and intramuscular injection in dogs.
      ). However, in previously studies, IN administration produced less effect on HR (only 18% decreases in HR were reported when the IN route was used) (
      • Micieli F.
      • Santangelo B.
      • Reynaud F.
      • et al.
      Sedative and cardiovascular effects of intranasal or intramuscular dexmedetomidine in healthy dogs.
      ). Since our aim was not to identify potential differences in cardiopulmonary variables, our study may be underpowered to detect a smaller effect produced by the IN route. Notably, fR increased when dexmedetomidine was administered IN, while HR showed a trend to higher values although blood pressures were probably not affected by either route.
      Dexmedetomidine produced analgesia as evidenced by increased MNTs following either administration route, with peak values matching those of the sedation.
      There are some limitations to our study. As already stated, the study was designed to evaluate the degree of sedation produced by dexmedetomidine and thus the effects on other studied variables were probably not appropriately addressed. Besides, this was a clinical study where dogs were anaesthetized for elective surgical procedures. Therefore, the observation period was limited to 45 minutes and thus the duration of sedation was unknown. Also, drug doses were not adjusted to the individual nasal conformation of different breeds of dog. However, no brachycephalic dogs were included in the present study. Finally, the pharmacokinetics of dexmedetomidine administered by either route were not determined neither was the agreement between plasma concentrations and the observed effects.

      Conclusions

      In summary, the effects of the IN administration of a relatively low dexmedetomidine dose of 5 μg kg–1 to healthy dogs did not differ from those produced by the IM route. Both routes provided an effective, smooth and predictable sedation with good tolerance. A clinically suitable sedation was produced allowing IV catheter placement before the administration of anaesthetic drugs and IV fluids.

      Author’s contributions

      VLR: study design, data acquisition, data interpretation, manuscript preparation, revision and approval. SCA and IAGS: study design, data interpretation, manuscript preparation, revision and approval. All authors read and approved the final version of the manuscript.

      Conflict of interest statement

      The authors declare no conflict of interest.

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