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Effects of intravenous dexmedetomidine infusion on local anaesthetic block: A spinal anaesthesia clinical model in dogs undergoing hind limb surgery
Research in Veterinary Science 124 (2019) 93–98
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Research in Veterinary Science journal homepage: www.elsevier.com/locate/rvsc
Effects of intravenous dexmedetomidine infusion on local anaesthetic block: A spinal anaesthesia clinical model in dogs undergoing hind limb surgery
T
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D. Sarottia, , R. Rabozzib, P. Francic a
Centro Veterinario Fossanese, Fossano, CN, Italy Clinica Veterinaria Roma Sud, Roma, RM, Italy c Dep. of Veterinary Science, University of Turin, Grugliasco, TO, Italy b
A R T I C LE I N FO
A B S T R A C T
Keywords: Spinal anaesthesia Dexmedetomidine Isoflurane Block duration Hypotension
The aim of this randomised, prospective clinical trial was to determine how the administration of a low dose of dexmedetomidine (DEX) by IV constant rate infusion, modified the duration of the nerve block in dogs undergoing spinal anaesthesia (SA) in a clinical setting. Forty-four dogs undergoing hind limb orthopaedic surgery in a day-surgery regime, maintained under anaesthesia with isoflurane plus SA, were randomly assigned to receive 1 μg/kg/h (IV) of DEX (group D) or not (group C). Spinal anaesthesia was performed with a hyperbaric solution of bupivacaine and morphine at the L5–6 interspace. Every mean arterial pressure (MAP) increase by 30% above the pre-skin incision value was considered an intraoperative analgesic failure and treated with a bolus of fentanyl as intraoperative rescue analgesia (iRA). Time free from iRA was analysed with a Kaplan-Maier survival curve. The ability to walk at 5 h from SA and the event of bradycardia (HR lower 60 beat per min) and hypotension (MAP value lower 60 mmHg) were recorded. The mean times at which iRA was required were 77.4 (3.2) in group C and 112.2 (8.6) in group D (Logrank test P = 0.038). In groups C and D hypotension incidence was 11/17 (65%) and 2/22 (9%), (P = 0.0004) and bradycardia 3/17 (18%) and 6/22 (27%) (P = 0.704), respectively. The ability to walk 5 h after SA was 14/14 (100%) and 13/14 (93%) in groups C and D, respectively. DEX infusion significantly prolonged the duration of the nociceptive nervous block without prolonging the motor block or increasing the bradycardia events.
1. Introduction To prolong the duration of the local anaesthetics (LA) block, many adjuvants such as opioids, alpha2-agonists, epinephrine, phenylephrine, ketamine and magnesium sulphate have been proposed (Axelsson and Kupta, 2009; Adami et al., 2016). Ideally the perfect adjuvant should extend the duration of the sensory block without increasing the offset of motor block and the local neurotoxicity risk. In humans alpha2-agonists, such as clonidine and dexmedetomidine (DEX) are commonly used to prolong the duration and to improve the quality of the sensory block, when regional anaesthesia is performed (Lundblad et al., 2016). These drugs can prolong the duration of the local anaesthetic block either if administered locally and intravenously (Staikou and Paraskeva, 2014; Trifa et al., 2018). In recent studies performed in humans (Abdallah et al., 2013) systemic administration of dexmedetomidine has shown to prolong the sensory spinal block, without proportionally increasing the duration of the motor block; however this effect has never been proven in dogs.
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Spinal anaesthesia (SA), due to its own intrinsic characteristics, can be considered a good model to study the clinical effect of drugs, which can alter the nervous block. SA is regarded as one of the most reliable regional anaesthetic techniques because the correct positioning of the needle is easy verifiable by the cerebral spinal fluid (CSF) outflow from the hub of the need and the LA, injected very close to the spinal cord and in a well delimitated space containing fluid, produces a block of short and predicable duration (Di Cianni et al., 2008; Saporito et al., 2018). Moreover, the intraoperative characteristics of this regional technique have been very well characterized in dogs when combined with general anaesthesia maintained with isoflurane or propofol (Sarotti et al., 2013; 2015). Our primary hypothesis was that a DEX constant rate infusion (CRI) in dogs anaesthetised with isoflurane and SA would provide a longer period free from intraoperative rescue analgesia (iRA) without prolonging the duration of the motor block. The secondary endpoint of our work was to evaluate the effect of DEX on the incidence of bradycardia and hypotension.
Correspondencing author. E-mail address: [email protected] (D. Sarotti).
https://doi.org/10.1016/j.rvsc.2019.03.001 Received 1 November 2018; Received in revised form 28 February 2019; Accepted 1 March 2019 0034-5288/ © 2019 Elsevier Ltd. All rights reserved.
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2. Materials and methods
2013 using the following equation: 0.3 BM (kg) + 0.05 SCL (cm). The SCL was recorded as the distance between the caudal part of the spinal process of L7 and the occipital bone. The morphine 1% (Morfina, Molteni) dose was 0.3 mg in dogs < 10 kg, 0.5 mg in dogs between 11 and 20 kg, and 1 mg in dogs over 20 kg. About 30 min before extubation, 0.2 mg/kg of meloxicam 5 mg/mL (Metacam, Boehringer Ingelheim) was administered SC to all dogs.
2.1. Animals We evaluated client-owned dogs, presenting to the Centro Veterinario Fossanese, from January 2016 to April 2017, for various scheduled surgical procedures involving the hind limb, belonging to American Society of Anaesthesiologists classification (ASA) lower than 3, > 6 months old, without infectious skin diseases affecting the lumbosacral area or a history of bleeding disorders. This study was approved by the Ethical Committee of the University of Padua (Prot. N. Prot. n.159597) and all owners gave their informed consent.
2.4. Treatment groups In group C general anaesthesia was maintained with isoflurane, and in group D with isoflurane and dexmedetomidine (Dexdomitor 0.5, Orion Pharma) at a CRI of 1 μg/kg/h starting after the intubation and infused for the entire duration of the intraoperative period. Median isoflurane ET (%) in the first h after spinal injection was calculated and recorded.
2.2. Study design The study was designed as a randomised, prospective clinical trial. Dogs were assigned to one of the two treatment groups according to a computer-generated randomization sequence. The estimated sample size required was 40 dogs to detect a difference in the primary endpoint (with a power of 80% and an alpha error of 5%) assuming an iRA incidence at 80 min from intrathecal injections of 45% and 10% for groups C and D respectively.
2.5. Exclusion criteria Exclusion criteria included the procedural failure of the SA and the lack of direct blood pressure data. Cases where DEX infusion was stopped because of severe bradycardia (see below) were excluded from the iRA evaluation. Postoperative ability to walk was not assessed in all dogs if they were not able to walk before surgery or bandaging prevented them.
2.3. Anaesthetic protocol and procedures Before induction of general anaesthesia, catheterisation of the cephalic vein was performed. General anaesthesia was then induced by administering fentanyl 2 μg/kg intravenously (Fentadon, Eurovet Animal Health BV) and propofol 1% (Proposure, Merial) to effect and maintained with isoflurane (IsoFlo, Aesica Queenborough) vaporised in an oxygen-air mixture and delivered via a circle system. After connecting the endotracheal tube to the breathing system, End-tidal isoflurane (ETiso) was maintained at 1.1–1.2% as target and optimized, when necessary, in order to suppress palpebral reflex, or obtain adequate muscle relaxation (as required by the surgeon). All patients included in this study received intermittent positive pressure ventilation (Cato, Draeger, Germany) and their metatarsal artery was catheterised to allow continuous measurement of the systolic (SAP), mean (MAP) and diastolic (DAP) arterial blood pressures. Lactated Ringer's solution (Ringer Lattato; Fresenius Kabi) was administered IV during anaesthesia to all dogs at 5 mL/kg/h. A multiparametric monitor (GE Datex Ohmeda AS3, Germany) was used to assess cardiovascular (SAP, MAP, DAP, and heart rate [HR]), and respiratory (end-tidal carbon dioxide, PE'CO2; peak inspiratory pressure, PIP; respiratory rate, RR; tidal volume, TV; inspired fraction of oxygen, FIO2; end-tidal isoflurane tension, PE'ISO) variables, as well as oesophageal temperature (T, °C). Data were manually recorded every 5 min until the end of anaesthesia. The body temperature was maintained above 35 °C during the perioperative period using an active heating system (Bair Hugger Warmer Model 505, Augustine Biomedical Design, MN, USA). In order to perform SA, once anaesthetised, dogs were positioned in lateral recumbency, and the skin over the L3-S1 vertebrae was aseptically prepared after clipping the hair. The lack of cerebral spinal fluid (CSF) outflow after three attempts was considered a procedural failure in SA. An attempt was considered every time the needle was positioned or re-positioned to strike the vertebral lamina. The intrathecal injection was administered using a paramedian approach at the level of the intervertebral space between L5 and L6 using a 75-mm-long 25 G Quincke needle (Spinal needle, Pic). Once the CSF outflow became visible in the hub of the needle, the intrathecal solution was injected over 20 s. The needle bevel always faced cranially during administration of the intrathecal solution. Once the injection was complete, dogs were maintained in lateral recumbency, with the pelvic limb to be operated on lowermost for at least 12 min. The dose of bupivacaine 0.5% (Bupisen iperbarica, Galenica Senese) to be administered was based on body mass (BM) and spinal cord length (SCL), according to Sarotti et al.,
2.6. Event definition and treatment Hypotension was defined when MAP value was lower than 60 mmHg for at least one min. When hypotension was noticed, the vaporizer setting was reduced if the clinical signs of the level of anaesthesia allowed it and a bolus of lactated Ringer's solution (3 mL/kg) was administered intravenously over one min and repeated if needed. Animals not fluid-responsive received a bolus of ephedrine (Efedrina, Galenica Senese) of 50 μg/kg until a maximal total dose of 200 μg/kg was reached. If the hypotension was not or only transitorily corrected by these treatments, a noradrenaline infusion at 0.1–1 μg/kg/min was administered. When the HR value was below 60 beats per min (bpm), it was defined as bradycardia. In the group C bradycardia events were treated with atropine at 20 μg/kg IV, while in the group D bradycardia events were not treated and when the HR was below 50 bpm the DEX CRI was stopped and the subject was excluded from further data evaluation. In both groups bradycardia was treated with atropine at 20 μg/ kg IV in hypotensive subjects. 2.7. Assessment of nociception and pain Intra-operatively, any 30% increase in MAP above baseline values, defined as the values recorded before skin incision, was considered indicative of nociception. When such increase was seen, 1 μg/kg IV of fentanyl was administered as iRA. Post-operatively, pain was evaluated with the short form of the Glasgow composite measure pain scale (Reid et al., 2007) as soon as the dogs were sufficiently conscious to respond to stimulation (vocal call and incitement to sit or stand up) and then ever 120–150 min until discharge. Cut-off values to administer 0.1 μg/ kg IM of buprenorphine as rescue analgesia (Buprenodale, Dales Pharmaceuticals) were every value > 5/20. 2.8. Motor block evaluation Postoperative ability to walk was evaluated at 5 and 8 h after intrathecal injection. 2.9. Statistical analysis Categorical variables were reported as frequencies and percentages 94
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Fig. 1. Consort flow diagram: patient recruitment, inclusion and exclusion criteria are reported.
and intrathecal injection, the time between intrathecal injection and skin incision (min), between the skin incision and the end of surgery (min) and the entire time of anaesthesia. No differences in the median isoflurane ET (%) calculated in the first 60 min after spinal injection were noted between groups (P = 0.9) as reported in Table 1. The overall iRA incidence in groups C and D was 7/17 (41%) and 6/ 19 (31%), respectively (P = 0.73). The comparison of survival curves was statistically different (Logrank test p = 0.038). The mean times (min) at which iRA was required in groups C and D were 77.4 (3.2) and 112.2 (8.6), respectively (95% CI was 71.0 to 83.7 in group C and 95.3 to 129.1 in group D). The iRA free probability related to time between groups was shown with a Kaplan-Meier curve in Fig. 2. In groups C and D, during the entire anaesthetic period, hypotension incidence was 11/17 (65%) and 2/22 (9%), (P = 0.0004) and bradycardia 3/17 (18%) and 6/22 (27%), respectively (P = 0.704). In three dogs DEX infusion was stopped due to detection of HR lower than 50 bpm and their results were excluded from the iRA and postoperative evaluation. Hemodynamic data (HR, SAP, MAP and DAP) before intrathecal injection (T0), at 10 min (T1) and 20 min after intrathecal injection (T2) are reported in Table 2. The MAP was higher in group D compared with group C at T0 (P = 0.008), T1 (P = 0.001) and T2 (P = 0.001). The HR was not different between groups at T0 (P = 0.157), T1 (P = 0.681) and T2 (P = 0.3). The hypotension incidence and bradycardia treatments in groups C and D are reported in
and differences between groups were analysed using the Fisher's exact test. Hemodynamic data before intrathecal injection (T0), at 10 min (T1) and 20 min (T2) later were checked for normal distribution by visual inspection of bar graphs and histograms and by using the Shapiro–Wilk test. Continuous data normally distributed were reported as mean and standard deviation (SD) and analysed with the Student's t-test. Data not normally distributed were reported as median and range (minimum–maximum). Dependent non parametric samples were analysed using the Wilcoxon test, independent ones with Mann–Whitney U test. The iRA probability during time between groups was compared with a Logrank (Mantel-Cox) test. The significance level was set at 5% for all statistical methods (MedCalc Software for Windows version12.5, Ostend, Belgium).
3. Results Forty-four dogs were enrolled in this study, 20 and 24 cases respectively in groups C and D. Intrathecal injection failed in 5/44 (11%) cases. The CONSORT diagram on patient recruitment, inclusion and exclusion criteria is reported in Fig. 1. The demographic data (breed, age, BM, SCL, ASA category and type of surgery) of both groups can be found in Appendix A1. In Table 1 we report procedural data concerning the dose of propofol for induction of anaesthesia, the bupivacaine and morphine dose used for neuraxial blockade, the time from induction 95
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Table 1 Procedural data in group D and C. No statistically differences were found in anaesthetic doses, time of anaesthesia and between intrathecal injection and discharge. ET (End-tidal).
Bupivacaine dose (mg) Bupivacaine dose related to BM (mg/kg) Bupivacaine dose related to SCL (mg/cm) Morphine dose (mg) Morphine dose related to BM (mg/kg) Propofol induction bolus (mg/kg) Median ET isoflurane (%) in the first h after spinal injection Median time between induction and intrathecal injection (min) Median time between intrathecal injection and skin incision (min) Median time between the intrathecal injection and the end of surgery (min) Median time of the entire anaesthesia (min) Median time between intrathecal injection and discharge (h)
p=0.1080
p=0.0008
p=0.031
100
50
11.0 (2.6–16.0) 0.44 (0.4–0.88) 0.15 (0.07–0.20) 1 (0.3–1) 0.04 (0.03–0.10) 5.5 (4.0–8.0) 1.1 (0.9–1.3) 25 (15–30) 23 (20–28) 85 (45–160) 105 (70–180) 7 (5–10)
10.8 (2.3–16.0) 0.43 (0.39–0.85) 0.13 (0.08–0.15) 1 (0.3–1) 0.04 (0.03–0.11) 5.0 (4.0–7.0) 1.0 (0.8–1.4) 22 (12–28) 25 (20–35) 80 (50–90) 101 (75–120) 7 (4–9)
0.86 0.42 0.50 0.63 0.6 0.43 0.9 0.7 0.4 0.65 0.5 0.6
HR (T1)Iso
HR (T0)Iso
HR (T1)Dx
HR (T0)Dx
MAP (T1)Iso
MAP (T0)Iso
MAP (T1)Dx
Administering a CRI of 1 μg/kg/h of DEX IV in dogs that underwent SA and received general anaesthesia with isoflurane prolongs the mean intraoperative time free from iRA by 45%, without causing a clinically relevant increase in the postoperative motor block at 5 and 8 h after the LA injection. To the best of our knowledge this is the first study providing evidence that DEX IV has such a profound effect on spinal block in dogs. Several mechanisms of action have been postulated to explain the adjuvant effect of alpha2-agonists on local anaesthetics and different sites of action have been proposed, such as supra-spinal, spinal and peripheral. The supra-spinal effect is due to the binding of the alpha2-receptor at the level of the locus ceruleus in the brainstem, which reduces the release of norepinephrine and inhibits sympathetic activity (Yaksh et al., 1993). The spinal effect results from the action of the alpha2-agonist drug at the level of the dorsal horn, which alters the modulation of the nociceptive impulse (Murrel et al., 2005). A peripheral effect was demonstrated in an experimental model at the perineural level, due to the blockade of the hyperpolarisation-activated cation (Ih) current, (Brummett et al., 2011). Another proposed mechanism regards the systemic uptake of local anaesthetic from the site of injection which would decrease because of the vasoconstrictor effect exerted by the alpha2-agonist (Honkavaara et al., 2012). Using a DEX infusion, the median time at which iRA was required (min) increased by 60 min without prolonging the motor block. This should be considered a relevant clinical advantage. However, this study, reporting only the ability to walk at 5 and 8 h after the spinal injection, may not be sensitive enough to detect more subtle differences between groups C and D. In fact, similar studies involving human patients have shown an increase in motor block duration (17%), when individuals undergoing SA received DEX infusion (Abdallah et al., 2013). Moreover, the limited number of animals enrolled in this study limits the possibility of detecting differences between the two groups regarding motor block duration. In this study, in order to simplify the anaesthetic protocol, DEX was infused at 1 μg/kg/h without a loading dose to limit the risk of bradycardia and hypertension. This method of infusion produced an increasing plasma concentration of DEX in the first period of infusion. Lin
Fig. 2. The iRA probability related to time between groups C and D is analysed with a Kaplan-Meier curve. The iRA probability was significantly different between groups for the entire study period (P = 0.038 Log-rank test). “Censored” refers to subjects for which no events (iRA) were required during the surgery period. Censored data in the graph are marked with a small vertical line. Table 2 Hemodynamic data [median (range)] for groups D and C before intrathecal injection (T0), 10 min (T1) and 20 min (T2) later. HR: heart rate; SAP: systolic arterial pressure; MAP: mean arterial pressure; DAP: diastolic arterial pressure. SAP, DAP and MAP are higher in group D at T0, T1 and T2.
SAP (T0) MAP (T0) DAP (T0) HR (T0) SAP (T1) MAP (T1) DAP (T1) HR (T1) SAP (T2) MAP (T2) DAP (T2) HR (T2)
p-Value
4. Discussion
0
MAP (T0)Dx
HR (bt/min) and MAP (mmHg)
p=0.0002
Group C (n = 17)
walk respectively in groups C and D (P = 1). At 8 h after intrathecal injection all dogs evaluated were able to walk. The median time of discharge in groups C and D was respectively 7 (4–9) and 7 (5–10) h, (P = 0.6). All dogs were evaluated with a Glasgow pain scale at 4 h from intrathecal anaesthesia, 8/17 (47%) and 9/19 (47%) at 6 h, 3/17 (18%) and 4/19 (21%) at 8 h, respectively in groups C and D. Median pain score was 2 (0–4) and 2 (0–3) at 4 h, 2 (0–4) and 2 (0–4) at 6 h and 2 (2–3) and 2 (1–4) at 8 h, respectively in groups C and D (P > 0.05 at 4, 6 and 8 h in groups C and D). Postoperative urinary retention, itchiness and neurological damage were not reported.
Hemodynamic changes after intrathecal injection 150
Group D (n = 22)
Group D (n = 22)
Group C (n = 17)
p-Value
105 (86–137) 73.5 (56–94) 61.5 (42–81) 85 (53–125) 104 (86–131) 72 (51–86) 57.5 (39–77) 73 (46–103) 102 (86–143) 71 (51–87) 60 (38–73) 79 (54–127)
94 (67–134) 69 (50–84) 55 (33–65) 103 (74–139) 90 (74–118) 61 (53–76) 48 (35–59) 75 (43–130) 89 (72–122) 63 (50–77) 49 (38–66) 86 (46–150)
0.030 0.008 0.007 0.157 0.006 0.001 0.001 0.681 0.002 0.001 0.002 0.3
Table 3. In group C HR and MAP decrease at 10 min after intrathecal injection (P = 0.0310 and P = 0.0008 respectively); in group D, HR decreases 10 min after intrathecal injection (P = 0.0002) but the MAP does not (P = 0.1080), Fig. 3. The ability to walk was evaluated in 14 dogs per group. At 5 h after intrathecal injection dogs 14/14 (100%) and 13/14 (93%) were able to 96
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Table 3 Hypotension and bradycardia incidence and relative definitive treatments in groups D and C. Hypotension incidence is higher in group C compared with group D (p = 0.0004). Group C (n = 17)
p-Value
Hypotension (%) Treatment of hypotension
2/22 (9%) 1 treated with atropine 20 μg/kg IV 1 treated with ephedrine 50 μg/kg IV
0.0004
Bradycardia (%) Treatment of bradycardia
6/22 (27%) 3 not treated 3 treated with atropine IV 20 μg/kg and stopping dexmedetomidine infusion
11/17 (65%) 7 treated with ephedrine IV 2 treated lightening general anaesthesia 1 treated with a bolus of fluid 1 treated with atropine 3/17 (18%) 2 not treated 1 treated with atropine IV 20 μg/kg IV
iRA survival probability (%)
Group D (n = 22)
baroceptor reflex responses due to DEX causing a vasoconstriction effect. The great reduction of hypotensive events in group D may be explained as a consequence of peripheral vasoconstriction (Murrel et al., 2005). Blood pressure remained within an acceptable range in dogs given 10 μg/kg of DEX and anaesthetised with either isoflurane or propofol (Kuusela et al., 2003), suggesting that the peripheral vasoconstrictor action of DEX predominates during isoflurane and propofol anaesthesia. Animals undergoing SA commonly have a relevant decrease in their blood pressure after intrathecal injection as found in group C. Surprisingly, in this study no effect on blood pressure was caused by the intrathecal block in group D. The sympathetic denervation to an extensive area of the body caused by SA may have been compensated by the direct peripheral vasoconstrictive effect of the DEX. Having started the infusion at the time of induction may have raised DEX concentration high enough to render peripheral vessel tone insensitive to the sympathetic central supply block. The anaesthetists involved in this work were not blind to the study treatment and they were free to manage the anaesthetic depth without a predetermined protocol. These limitations may have been a source of bias in the results of this work. Moreover we cannot exclude that the hemodynamic treatments administered during surgery period could have interfered with our method to detect the intraoperative analgesic efficacy (30% increase in MAP above baseline values), even though almost all hemodynamic treatments in our study were performed before the skin incision. Events of urinary retention were not reported in this study and even though all owners received indications on how to recognize it, this complication may have gone unseen in some subjects.
110 100
Group D
90 80
Group C
70 60 50 40 30 20 10 0 0
0.7042
10 20 30 40 50 60 70 80 90 100 110 120 130 140
Time (minutes) Fig. 3. Mean arterial pressure (MAP) and Heart rate (HR) comparison in group C and D before intrathecal injection (T0), at 10 min after intrathecal injection (T1). In group C MAP and HR decrease after intrathecal injection (respectively P = 0.031; P = 0.0008); in group D HR decreases after intrathecal injection (P = 0.0002) but no MAP decrease was detected (P = 0.108).
et al. (2008) studied the hemodynamic and pharmacokinetic data produced by a similar CRI of DEX (1.2 μg/kg/h) in experimental dogs, undergoing isoflurane or propofol anaesthesia. They found that vascular resistance and blood pressure increased and HR and CO decreased. In Lin et al.'s study, dogs maintained under anaesthesia with isoflurane received a loading dose of DEX followed by a CRI, producing a plasma concentration ranging from 0.40 to 0.47 ng/mL. The plasma concentration in our study could have been lower because of the lack of loading dose, particularly when the SA was executed. This low plasma concentration of DEX may have been one of the reasons for the very mild effect on HR found. The time between the beginning of the DEX infusion and the intrathecal injection was not standardised and this may have introduced a further degree of variability in the plasma concentration of DEX when SA was performed. Even if not statistically significant, more dogs in group D were excluded from the study due to bradycardia than in group C. Interestingly, they developed such a condition soon after spinal injection rather than at the end of anaesthesia after a prolonged infusion of DEX. It is well known that SA can cause bradycardia, blocking the sympathetic supply to the heart and this has also been reported in dogs (Sarotti et al., 2016). Reduction of the HR by SA is also detectable in group C considering the HR at T0 and T1. DEX infusion can be seen as a contributing factor for the development of perioperative bradycardia. On the other hand, vasodilationinduced by the sympathetic spinal block might have mitigated the
5. Conclusions DEX infusion in dogs undergoing SA and maintained under anaesthesia with isoflurane, as described in this study, was found to prolong the nociceptive block (time free from iRA), without significantly increasing motor function impairment or bradycardia. Conflict of interest statement None of the authors have financial or personal relationships with individuals or organizations that could inappropriately influence or bias the content of the paper. Acknowledgements Preliminary results were presented as an Abstract at the Autumn AVA meeting of Berlin (2017)
Appendix A. Appendix Demographic data of dogs [median (range)] that met the inclusion criteria for groups C and D in which SA was performed successfully. BM: body mass; SCL: spine cord length; ASA, American Society of Anaesthesiologists. TPLO (Tibial Plate Levelling Osteotomy); FHNO (Femoral Head and Neck 97
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Ostectomy)
Breed (n)
Age (month) BM (kg) SCL (cm) Type of surgery
ASA Category (n)
Group D (n = 22)
Group C (n = 17)
p-Value
5 Mix breed 3 Labrador retriever 2 Pincher 2 German Shepherd 2 Dachshund 8 Other breed 48 (10−132) 26 (3–40) 70 (35–80) 8 TPLO 4 Osteosynthesis of a femoral fracture 4 FHNO 3 Medial patellar luxation repair 2 Hind limb amputation 1 Osteosynthesis of a tibial fracture ASA I (15) ASA II (7)
10 Mix breed 4 Labrador retriever 3 Other breed
Not evaluated
84 (11–168) 27 (3–40) 64 (30–80) 9 TPLO 3 FHNO 3 Medial patellar luxation repair 2 Osteosynthesis of a femoral fracture
0.10 0.66 0.90 Not evaluated
ASA I (12) ASA II (5)
0.92
Murrell, J.C., Hellebrekers, L.J., 2005. Medetomidine and DEX: a review of cardiovascular effects and antinociceptive properties in the dog. Vet. Anaesth. Analg. 32, 117–127. Reid, J., Nolan, A.M., Hughes, J.M.L., Lascelles, D., Pawson, P., Scott, E.M., 2007. Development of the short-form Glasgow composite measure pain scale (CMPS-SF) and derivation of an analgesic intervention score. Anim. welf. 97–104 suppl 1. Saporito, A., Ceppi, M., Perren, A., La Regina, D., Cafarotti, S., Borgeat, A., Aguirre, J., Van De Velde, M., Teunkens, A.J., 2018. Does spinal chloroprocaine pharmacokinetic profile actually translate into a clinical advantage in terms of clinical outcomes when compared to low-dose spinal bupivacaine? A systematic review and meta-analysis. J. Clin. Anesth. 52, 99–104. Sarotti, D., Rabozzi, R., Franci, P., 2013. A retrospective study of efficacy and side effects of intrathecal administration of hyperbaric bupivacaine and morphine solution in 39 dogs undergoing hind limb orthopaedic surgery. Vet. Anaesth. Analg. 40, 220–224. Sarotti, D., Rabozzi, R., Franci, P., 2015. Comparison of epidural versus intrathecal anaesthesia in dogs undergoing pelvic limb orthopaedic surgery. Vet. Anaesth. Analg. 42, 405–413. Sarotti, D., Rabozzi, R., Franci, P., 2016. Impact evaluation of two different general anesthesia protocols (TIVA with propofol vs isoflurane) on the total number of interventions to treat cardiovascular depression or arousal/movement episodes in dogs undergoing orthopedic surgery receiving an intrathecal anesthesia. J. Vet. Med. Sci. 78, 1549–1555. Staikou, C., Paraskeva, A., 2014. The effects of intrathecal and systemic adjuvants on subarachnoid block. Minerva Anestesiol. 80, 96–112. Trifa, M., Tumin, D., Tobias, J.D., 2018. Dexmedetomidine as an adjunct for caudal anesthesia and analgesia in children. Minerva Anestesiol. 84, 836–847. Yaksh, T.L., Jage, J., Takano, Y., 1993. Pharmacokinetics and pharmacodynamics of medullar agents. The spinal actions of α-2 adrenergic agonists as analgesics. Clin. Anaesthesiol. 7, 597–614.
References Abdallah, F.W., Abrishami, A., Brull, R., 2013. The facilitatory effects of intravenous dexmedetomine on the duration of spinal anesthesia: a systematic review and metaanalysis. Anesth. Analg. 117, 271–278. Adami, C., Casoni, D., Noussitou, F., Rytz, U., Spadavecchia, C., 2016. Addition of magnesium sulphate to ropivacaine for spinal analgesia in dogs undergoing tibial plateau levelling osteotomy. Vet. J. 209, 163–168. Axelsoon, K., Gupta, A., 2009. Local anaesthetic adjuvants: neuraxial versus peripheral nerve block. Curr. Opin. Anaesth. 22, 649–654. Brummett, C.M., Hong, E.K., Janda, A.M., Amodeo, F.S., Lydic, R., 2011. Perineural dexmedetomidine added to ropivacaine for sciatic nerve block in rats prolongs the duration of analgesia by blocking the hyperpolarization activated cation current. Anesthesiology 115, 836–843. Di Cianni, S., Rossi, M., Casati, A., Cocco, C., Fanelli, G., 2008. Spinal anesthesia: an evergreen technique. Acta Biomed 79, 9–17. Honkavaara, J., Restitutti, F., Raekallio, M., Salla, K., Kuusela, E., Ranta-Panula, V., Rinne, V., Vainio, O., Scheinin, M., 2012. Influence of MK-467, a peripherally acting α2-adrenoceptor antagonist on the disposition of intravenous dexmedetomidine in dogs. Drug Metab. Dispos. 40, 445–449. Kuusela, E., Vainio, O., Short, C.E., Leppäluoto, J., Huttunen, P., Ström, S., Huju, V., Valtonen, A., Raekallio, M., 2003. A comparison of propofol infusion and propofol/ isoflurane anaesthesia in dexmedetomidine premedicated dogs. J. Vet. Pharmacol. Ther. 26, 199–204. Lin, G.Y., Robben, J.H., Murrell, J.C., Aspegrén, J., McKusick, B.C., Hellebrekers, L.J., 2008. Dexmedetomidine constant rate infusion for 24 hours during and after propofol or isoflurane anaesthesia in dogs. Vet. Anaesth. Analg. 5, 141–153. Lundblad, M., Lönnqvist, P.A., 2016. Adjunct analgesic drugs to local anaesthetics for neuroaxial blocks in children. Curr. Opin. Anaesthesiol. 29, 626–631.
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Research in Veterinary Science journal homepage: www.elsevier.com/locate/rvsc
Effects of intravenous dexmedetomidine infusion on local anaesthetic block: A spinal anaesthesia clinical model in dogs undergoing hind limb surgery
T
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D. Sarottia, , R. Rabozzib, P. Francic a
Centro Veterinario Fossanese, Fossano, CN, Italy Clinica Veterinaria Roma Sud, Roma, RM, Italy c Dep. of Veterinary Science, University of Turin, Grugliasco, TO, Italy b
A R T I C LE I N FO
A B S T R A C T
Keywords: Spinal anaesthesia Dexmedetomidine Isoflurane Block duration Hypotension
The aim of this randomised, prospective clinical trial was to determine how the administration of a low dose of dexmedetomidine (DEX) by IV constant rate infusion, modified the duration of the nerve block in dogs undergoing spinal anaesthesia (SA) in a clinical setting. Forty-four dogs undergoing hind limb orthopaedic surgery in a day-surgery regime, maintained under anaesthesia with isoflurane plus SA, were randomly assigned to receive 1 μg/kg/h (IV) of DEX (group D) or not (group C). Spinal anaesthesia was performed with a hyperbaric solution of bupivacaine and morphine at the L5–6 interspace. Every mean arterial pressure (MAP) increase by 30% above the pre-skin incision value was considered an intraoperative analgesic failure and treated with a bolus of fentanyl as intraoperative rescue analgesia (iRA). Time free from iRA was analysed with a Kaplan-Maier survival curve. The ability to walk at 5 h from SA and the event of bradycardia (HR lower 60 beat per min) and hypotension (MAP value lower 60 mmHg) were recorded. The mean times at which iRA was required were 77.4 (3.2) in group C and 112.2 (8.6) in group D (Logrank test P = 0.038). In groups C and D hypotension incidence was 11/17 (65%) and 2/22 (9%), (P = 0.0004) and bradycardia 3/17 (18%) and 6/22 (27%) (P = 0.704), respectively. The ability to walk 5 h after SA was 14/14 (100%) and 13/14 (93%) in groups C and D, respectively. DEX infusion significantly prolonged the duration of the nociceptive nervous block without prolonging the motor block or increasing the bradycardia events.
1. Introduction To prolong the duration of the local anaesthetics (LA) block, many adjuvants such as opioids, alpha2-agonists, epinephrine, phenylephrine, ketamine and magnesium sulphate have been proposed (Axelsson and Kupta, 2009; Adami et al., 2016). Ideally the perfect adjuvant should extend the duration of the sensory block without increasing the offset of motor block and the local neurotoxicity risk. In humans alpha2-agonists, such as clonidine and dexmedetomidine (DEX) are commonly used to prolong the duration and to improve the quality of the sensory block, when regional anaesthesia is performed (Lundblad et al., 2016). These drugs can prolong the duration of the local anaesthetic block either if administered locally and intravenously (Staikou and Paraskeva, 2014; Trifa et al., 2018). In recent studies performed in humans (Abdallah et al., 2013) systemic administration of dexmedetomidine has shown to prolong the sensory spinal block, without proportionally increasing the duration of the motor block; however this effect has never been proven in dogs.
⁎
Spinal anaesthesia (SA), due to its own intrinsic characteristics, can be considered a good model to study the clinical effect of drugs, which can alter the nervous block. SA is regarded as one of the most reliable regional anaesthetic techniques because the correct positioning of the needle is easy verifiable by the cerebral spinal fluid (CSF) outflow from the hub of the need and the LA, injected very close to the spinal cord and in a well delimitated space containing fluid, produces a block of short and predicable duration (Di Cianni et al., 2008; Saporito et al., 2018). Moreover, the intraoperative characteristics of this regional technique have been very well characterized in dogs when combined with general anaesthesia maintained with isoflurane or propofol (Sarotti et al., 2013; 2015). Our primary hypothesis was that a DEX constant rate infusion (CRI) in dogs anaesthetised with isoflurane and SA would provide a longer period free from intraoperative rescue analgesia (iRA) without prolonging the duration of the motor block. The secondary endpoint of our work was to evaluate the effect of DEX on the incidence of bradycardia and hypotension.
Correspondencing author. E-mail address: [email protected] (D. Sarotti).
https://doi.org/10.1016/j.rvsc.2019.03.001 Received 1 November 2018; Received in revised form 28 February 2019; Accepted 1 March 2019 0034-5288/ © 2019 Elsevier Ltd. All rights reserved.
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2. Materials and methods
2013 using the following equation: 0.3 BM (kg) + 0.05 SCL (cm). The SCL was recorded as the distance between the caudal part of the spinal process of L7 and the occipital bone. The morphine 1% (Morfina, Molteni) dose was 0.3 mg in dogs < 10 kg, 0.5 mg in dogs between 11 and 20 kg, and 1 mg in dogs over 20 kg. About 30 min before extubation, 0.2 mg/kg of meloxicam 5 mg/mL (Metacam, Boehringer Ingelheim) was administered SC to all dogs.
2.1. Animals We evaluated client-owned dogs, presenting to the Centro Veterinario Fossanese, from January 2016 to April 2017, for various scheduled surgical procedures involving the hind limb, belonging to American Society of Anaesthesiologists classification (ASA) lower than 3, > 6 months old, without infectious skin diseases affecting the lumbosacral area or a history of bleeding disorders. This study was approved by the Ethical Committee of the University of Padua (Prot. N. Prot. n.159597) and all owners gave their informed consent.
2.4. Treatment groups In group C general anaesthesia was maintained with isoflurane, and in group D with isoflurane and dexmedetomidine (Dexdomitor 0.5, Orion Pharma) at a CRI of 1 μg/kg/h starting after the intubation and infused for the entire duration of the intraoperative period. Median isoflurane ET (%) in the first h after spinal injection was calculated and recorded.
2.2. Study design The study was designed as a randomised, prospective clinical trial. Dogs were assigned to one of the two treatment groups according to a computer-generated randomization sequence. The estimated sample size required was 40 dogs to detect a difference in the primary endpoint (with a power of 80% and an alpha error of 5%) assuming an iRA incidence at 80 min from intrathecal injections of 45% and 10% for groups C and D respectively.
2.5. Exclusion criteria Exclusion criteria included the procedural failure of the SA and the lack of direct blood pressure data. Cases where DEX infusion was stopped because of severe bradycardia (see below) were excluded from the iRA evaluation. Postoperative ability to walk was not assessed in all dogs if they were not able to walk before surgery or bandaging prevented them.
2.3. Anaesthetic protocol and procedures Before induction of general anaesthesia, catheterisation of the cephalic vein was performed. General anaesthesia was then induced by administering fentanyl 2 μg/kg intravenously (Fentadon, Eurovet Animal Health BV) and propofol 1% (Proposure, Merial) to effect and maintained with isoflurane (IsoFlo, Aesica Queenborough) vaporised in an oxygen-air mixture and delivered via a circle system. After connecting the endotracheal tube to the breathing system, End-tidal isoflurane (ETiso) was maintained at 1.1–1.2% as target and optimized, when necessary, in order to suppress palpebral reflex, or obtain adequate muscle relaxation (as required by the surgeon). All patients included in this study received intermittent positive pressure ventilation (Cato, Draeger, Germany) and their metatarsal artery was catheterised to allow continuous measurement of the systolic (SAP), mean (MAP) and diastolic (DAP) arterial blood pressures. Lactated Ringer's solution (Ringer Lattato; Fresenius Kabi) was administered IV during anaesthesia to all dogs at 5 mL/kg/h. A multiparametric monitor (GE Datex Ohmeda AS3, Germany) was used to assess cardiovascular (SAP, MAP, DAP, and heart rate [HR]), and respiratory (end-tidal carbon dioxide, PE'CO2; peak inspiratory pressure, PIP; respiratory rate, RR; tidal volume, TV; inspired fraction of oxygen, FIO2; end-tidal isoflurane tension, PE'ISO) variables, as well as oesophageal temperature (T, °C). Data were manually recorded every 5 min until the end of anaesthesia. The body temperature was maintained above 35 °C during the perioperative period using an active heating system (Bair Hugger Warmer Model 505, Augustine Biomedical Design, MN, USA). In order to perform SA, once anaesthetised, dogs were positioned in lateral recumbency, and the skin over the L3-S1 vertebrae was aseptically prepared after clipping the hair. The lack of cerebral spinal fluid (CSF) outflow after three attempts was considered a procedural failure in SA. An attempt was considered every time the needle was positioned or re-positioned to strike the vertebral lamina. The intrathecal injection was administered using a paramedian approach at the level of the intervertebral space between L5 and L6 using a 75-mm-long 25 G Quincke needle (Spinal needle, Pic). Once the CSF outflow became visible in the hub of the needle, the intrathecal solution was injected over 20 s. The needle bevel always faced cranially during administration of the intrathecal solution. Once the injection was complete, dogs were maintained in lateral recumbency, with the pelvic limb to be operated on lowermost for at least 12 min. The dose of bupivacaine 0.5% (Bupisen iperbarica, Galenica Senese) to be administered was based on body mass (BM) and spinal cord length (SCL), according to Sarotti et al.,
2.6. Event definition and treatment Hypotension was defined when MAP value was lower than 60 mmHg for at least one min. When hypotension was noticed, the vaporizer setting was reduced if the clinical signs of the level of anaesthesia allowed it and a bolus of lactated Ringer's solution (3 mL/kg) was administered intravenously over one min and repeated if needed. Animals not fluid-responsive received a bolus of ephedrine (Efedrina, Galenica Senese) of 50 μg/kg until a maximal total dose of 200 μg/kg was reached. If the hypotension was not or only transitorily corrected by these treatments, a noradrenaline infusion at 0.1–1 μg/kg/min was administered. When the HR value was below 60 beats per min (bpm), it was defined as bradycardia. In the group C bradycardia events were treated with atropine at 20 μg/kg IV, while in the group D bradycardia events were not treated and when the HR was below 50 bpm the DEX CRI was stopped and the subject was excluded from further data evaluation. In both groups bradycardia was treated with atropine at 20 μg/ kg IV in hypotensive subjects. 2.7. Assessment of nociception and pain Intra-operatively, any 30% increase in MAP above baseline values, defined as the values recorded before skin incision, was considered indicative of nociception. When such increase was seen, 1 μg/kg IV of fentanyl was administered as iRA. Post-operatively, pain was evaluated with the short form of the Glasgow composite measure pain scale (Reid et al., 2007) as soon as the dogs were sufficiently conscious to respond to stimulation (vocal call and incitement to sit or stand up) and then ever 120–150 min until discharge. Cut-off values to administer 0.1 μg/ kg IM of buprenorphine as rescue analgesia (Buprenodale, Dales Pharmaceuticals) were every value > 5/20. 2.8. Motor block evaluation Postoperative ability to walk was evaluated at 5 and 8 h after intrathecal injection. 2.9. Statistical analysis Categorical variables were reported as frequencies and percentages 94
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Fig. 1. Consort flow diagram: patient recruitment, inclusion and exclusion criteria are reported.
and intrathecal injection, the time between intrathecal injection and skin incision (min), between the skin incision and the end of surgery (min) and the entire time of anaesthesia. No differences in the median isoflurane ET (%) calculated in the first 60 min after spinal injection were noted between groups (P = 0.9) as reported in Table 1. The overall iRA incidence in groups C and D was 7/17 (41%) and 6/ 19 (31%), respectively (P = 0.73). The comparison of survival curves was statistically different (Logrank test p = 0.038). The mean times (min) at which iRA was required in groups C and D were 77.4 (3.2) and 112.2 (8.6), respectively (95% CI was 71.0 to 83.7 in group C and 95.3 to 129.1 in group D). The iRA free probability related to time between groups was shown with a Kaplan-Meier curve in Fig. 2. In groups C and D, during the entire anaesthetic period, hypotension incidence was 11/17 (65%) and 2/22 (9%), (P = 0.0004) and bradycardia 3/17 (18%) and 6/22 (27%), respectively (P = 0.704). In three dogs DEX infusion was stopped due to detection of HR lower than 50 bpm and their results were excluded from the iRA and postoperative evaluation. Hemodynamic data (HR, SAP, MAP and DAP) before intrathecal injection (T0), at 10 min (T1) and 20 min after intrathecal injection (T2) are reported in Table 2. The MAP was higher in group D compared with group C at T0 (P = 0.008), T1 (P = 0.001) and T2 (P = 0.001). The HR was not different between groups at T0 (P = 0.157), T1 (P = 0.681) and T2 (P = 0.3). The hypotension incidence and bradycardia treatments in groups C and D are reported in
and differences between groups were analysed using the Fisher's exact test. Hemodynamic data before intrathecal injection (T0), at 10 min (T1) and 20 min (T2) later were checked for normal distribution by visual inspection of bar graphs and histograms and by using the Shapiro–Wilk test. Continuous data normally distributed were reported as mean and standard deviation (SD) and analysed with the Student's t-test. Data not normally distributed were reported as median and range (minimum–maximum). Dependent non parametric samples were analysed using the Wilcoxon test, independent ones with Mann–Whitney U test. The iRA probability during time between groups was compared with a Logrank (Mantel-Cox) test. The significance level was set at 5% for all statistical methods (MedCalc Software for Windows version12.5, Ostend, Belgium).
3. Results Forty-four dogs were enrolled in this study, 20 and 24 cases respectively in groups C and D. Intrathecal injection failed in 5/44 (11%) cases. The CONSORT diagram on patient recruitment, inclusion and exclusion criteria is reported in Fig. 1. The demographic data (breed, age, BM, SCL, ASA category and type of surgery) of both groups can be found in Appendix A1. In Table 1 we report procedural data concerning the dose of propofol for induction of anaesthesia, the bupivacaine and morphine dose used for neuraxial blockade, the time from induction 95
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Table 1 Procedural data in group D and C. No statistically differences were found in anaesthetic doses, time of anaesthesia and between intrathecal injection and discharge. ET (End-tidal).
Bupivacaine dose (mg) Bupivacaine dose related to BM (mg/kg) Bupivacaine dose related to SCL (mg/cm) Morphine dose (mg) Morphine dose related to BM (mg/kg) Propofol induction bolus (mg/kg) Median ET isoflurane (%) in the first h after spinal injection Median time between induction and intrathecal injection (min) Median time between intrathecal injection and skin incision (min) Median time between the intrathecal injection and the end of surgery (min) Median time of the entire anaesthesia (min) Median time between intrathecal injection and discharge (h)
p=0.1080
p=0.0008
p=0.031
100
50
11.0 (2.6–16.0) 0.44 (0.4–0.88) 0.15 (0.07–0.20) 1 (0.3–1) 0.04 (0.03–0.10) 5.5 (4.0–8.0) 1.1 (0.9–1.3) 25 (15–30) 23 (20–28) 85 (45–160) 105 (70–180) 7 (5–10)
10.8 (2.3–16.0) 0.43 (0.39–0.85) 0.13 (0.08–0.15) 1 (0.3–1) 0.04 (0.03–0.11) 5.0 (4.0–7.0) 1.0 (0.8–1.4) 22 (12–28) 25 (20–35) 80 (50–90) 101 (75–120) 7 (4–9)
0.86 0.42 0.50 0.63 0.6 0.43 0.9 0.7 0.4 0.65 0.5 0.6
HR (T1)Iso
HR (T0)Iso
HR (T1)Dx
HR (T0)Dx
MAP (T1)Iso
MAP (T0)Iso
MAP (T1)Dx
Administering a CRI of 1 μg/kg/h of DEX IV in dogs that underwent SA and received general anaesthesia with isoflurane prolongs the mean intraoperative time free from iRA by 45%, without causing a clinically relevant increase in the postoperative motor block at 5 and 8 h after the LA injection. To the best of our knowledge this is the first study providing evidence that DEX IV has such a profound effect on spinal block in dogs. Several mechanisms of action have been postulated to explain the adjuvant effect of alpha2-agonists on local anaesthetics and different sites of action have been proposed, such as supra-spinal, spinal and peripheral. The supra-spinal effect is due to the binding of the alpha2-receptor at the level of the locus ceruleus in the brainstem, which reduces the release of norepinephrine and inhibits sympathetic activity (Yaksh et al., 1993). The spinal effect results from the action of the alpha2-agonist drug at the level of the dorsal horn, which alters the modulation of the nociceptive impulse (Murrel et al., 2005). A peripheral effect was demonstrated in an experimental model at the perineural level, due to the blockade of the hyperpolarisation-activated cation (Ih) current, (Brummett et al., 2011). Another proposed mechanism regards the systemic uptake of local anaesthetic from the site of injection which would decrease because of the vasoconstrictor effect exerted by the alpha2-agonist (Honkavaara et al., 2012). Using a DEX infusion, the median time at which iRA was required (min) increased by 60 min without prolonging the motor block. This should be considered a relevant clinical advantage. However, this study, reporting only the ability to walk at 5 and 8 h after the spinal injection, may not be sensitive enough to detect more subtle differences between groups C and D. In fact, similar studies involving human patients have shown an increase in motor block duration (17%), when individuals undergoing SA received DEX infusion (Abdallah et al., 2013). Moreover, the limited number of animals enrolled in this study limits the possibility of detecting differences between the two groups regarding motor block duration. In this study, in order to simplify the anaesthetic protocol, DEX was infused at 1 μg/kg/h without a loading dose to limit the risk of bradycardia and hypertension. This method of infusion produced an increasing plasma concentration of DEX in the first period of infusion. Lin
Fig. 2. The iRA probability related to time between groups C and D is analysed with a Kaplan-Meier curve. The iRA probability was significantly different between groups for the entire study period (P = 0.038 Log-rank test). “Censored” refers to subjects for which no events (iRA) were required during the surgery period. Censored data in the graph are marked with a small vertical line. Table 2 Hemodynamic data [median (range)] for groups D and C before intrathecal injection (T0), 10 min (T1) and 20 min (T2) later. HR: heart rate; SAP: systolic arterial pressure; MAP: mean arterial pressure; DAP: diastolic arterial pressure. SAP, DAP and MAP are higher in group D at T0, T1 and T2.
SAP (T0) MAP (T0) DAP (T0) HR (T0) SAP (T1) MAP (T1) DAP (T1) HR (T1) SAP (T2) MAP (T2) DAP (T2) HR (T2)
p-Value
4. Discussion
0
MAP (T0)Dx
HR (bt/min) and MAP (mmHg)
p=0.0002
Group C (n = 17)
walk respectively in groups C and D (P = 1). At 8 h after intrathecal injection all dogs evaluated were able to walk. The median time of discharge in groups C and D was respectively 7 (4–9) and 7 (5–10) h, (P = 0.6). All dogs were evaluated with a Glasgow pain scale at 4 h from intrathecal anaesthesia, 8/17 (47%) and 9/19 (47%) at 6 h, 3/17 (18%) and 4/19 (21%) at 8 h, respectively in groups C and D. Median pain score was 2 (0–4) and 2 (0–3) at 4 h, 2 (0–4) and 2 (0–4) at 6 h and 2 (2–3) and 2 (1–4) at 8 h, respectively in groups C and D (P > 0.05 at 4, 6 and 8 h in groups C and D). Postoperative urinary retention, itchiness and neurological damage were not reported.
Hemodynamic changes after intrathecal injection 150
Group D (n = 22)
Group D (n = 22)
Group C (n = 17)
p-Value
105 (86–137) 73.5 (56–94) 61.5 (42–81) 85 (53–125) 104 (86–131) 72 (51–86) 57.5 (39–77) 73 (46–103) 102 (86–143) 71 (51–87) 60 (38–73) 79 (54–127)
94 (67–134) 69 (50–84) 55 (33–65) 103 (74–139) 90 (74–118) 61 (53–76) 48 (35–59) 75 (43–130) 89 (72–122) 63 (50–77) 49 (38–66) 86 (46–150)
0.030 0.008 0.007 0.157 0.006 0.001 0.001 0.681 0.002 0.001 0.002 0.3
Table 3. In group C HR and MAP decrease at 10 min after intrathecal injection (P = 0.0310 and P = 0.0008 respectively); in group D, HR decreases 10 min after intrathecal injection (P = 0.0002) but the MAP does not (P = 0.1080), Fig. 3. The ability to walk was evaluated in 14 dogs per group. At 5 h after intrathecal injection dogs 14/14 (100%) and 13/14 (93%) were able to 96
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Table 3 Hypotension and bradycardia incidence and relative definitive treatments in groups D and C. Hypotension incidence is higher in group C compared with group D (p = 0.0004). Group C (n = 17)
p-Value
Hypotension (%) Treatment of hypotension
2/22 (9%) 1 treated with atropine 20 μg/kg IV 1 treated with ephedrine 50 μg/kg IV
0.0004
Bradycardia (%) Treatment of bradycardia
6/22 (27%) 3 not treated 3 treated with atropine IV 20 μg/kg and stopping dexmedetomidine infusion
11/17 (65%) 7 treated with ephedrine IV 2 treated lightening general anaesthesia 1 treated with a bolus of fluid 1 treated with atropine 3/17 (18%) 2 not treated 1 treated with atropine IV 20 μg/kg IV
iRA survival probability (%)
Group D (n = 22)
baroceptor reflex responses due to DEX causing a vasoconstriction effect. The great reduction of hypotensive events in group D may be explained as a consequence of peripheral vasoconstriction (Murrel et al., 2005). Blood pressure remained within an acceptable range in dogs given 10 μg/kg of DEX and anaesthetised with either isoflurane or propofol (Kuusela et al., 2003), suggesting that the peripheral vasoconstrictor action of DEX predominates during isoflurane and propofol anaesthesia. Animals undergoing SA commonly have a relevant decrease in their blood pressure after intrathecal injection as found in group C. Surprisingly, in this study no effect on blood pressure was caused by the intrathecal block in group D. The sympathetic denervation to an extensive area of the body caused by SA may have been compensated by the direct peripheral vasoconstrictive effect of the DEX. Having started the infusion at the time of induction may have raised DEX concentration high enough to render peripheral vessel tone insensitive to the sympathetic central supply block. The anaesthetists involved in this work were not blind to the study treatment and they were free to manage the anaesthetic depth without a predetermined protocol. These limitations may have been a source of bias in the results of this work. Moreover we cannot exclude that the hemodynamic treatments administered during surgery period could have interfered with our method to detect the intraoperative analgesic efficacy (30% increase in MAP above baseline values), even though almost all hemodynamic treatments in our study were performed before the skin incision. Events of urinary retention were not reported in this study and even though all owners received indications on how to recognize it, this complication may have gone unseen in some subjects.
110 100
Group D
90 80
Group C
70 60 50 40 30 20 10 0 0
0.7042
10 20 30 40 50 60 70 80 90 100 110 120 130 140
Time (minutes) Fig. 3. Mean arterial pressure (MAP) and Heart rate (HR) comparison in group C and D before intrathecal injection (T0), at 10 min after intrathecal injection (T1). In group C MAP and HR decrease after intrathecal injection (respectively P = 0.031; P = 0.0008); in group D HR decreases after intrathecal injection (P = 0.0002) but no MAP decrease was detected (P = 0.108).
et al. (2008) studied the hemodynamic and pharmacokinetic data produced by a similar CRI of DEX (1.2 μg/kg/h) in experimental dogs, undergoing isoflurane or propofol anaesthesia. They found that vascular resistance and blood pressure increased and HR and CO decreased. In Lin et al.'s study, dogs maintained under anaesthesia with isoflurane received a loading dose of DEX followed by a CRI, producing a plasma concentration ranging from 0.40 to 0.47 ng/mL. The plasma concentration in our study could have been lower because of the lack of loading dose, particularly when the SA was executed. This low plasma concentration of DEX may have been one of the reasons for the very mild effect on HR found. The time between the beginning of the DEX infusion and the intrathecal injection was not standardised and this may have introduced a further degree of variability in the plasma concentration of DEX when SA was performed. Even if not statistically significant, more dogs in group D were excluded from the study due to bradycardia than in group C. Interestingly, they developed such a condition soon after spinal injection rather than at the end of anaesthesia after a prolonged infusion of DEX. It is well known that SA can cause bradycardia, blocking the sympathetic supply to the heart and this has also been reported in dogs (Sarotti et al., 2016). Reduction of the HR by SA is also detectable in group C considering the HR at T0 and T1. DEX infusion can be seen as a contributing factor for the development of perioperative bradycardia. On the other hand, vasodilationinduced by the sympathetic spinal block might have mitigated the
5. Conclusions DEX infusion in dogs undergoing SA and maintained under anaesthesia with isoflurane, as described in this study, was found to prolong the nociceptive block (time free from iRA), without significantly increasing motor function impairment or bradycardia. Conflict of interest statement None of the authors have financial or personal relationships with individuals or organizations that could inappropriately influence or bias the content of the paper. Acknowledgements Preliminary results were presented as an Abstract at the Autumn AVA meeting of Berlin (2017)
Appendix A. Appendix Demographic data of dogs [median (range)] that met the inclusion criteria for groups C and D in which SA was performed successfully. BM: body mass; SCL: spine cord length; ASA, American Society of Anaesthesiologists. TPLO (Tibial Plate Levelling Osteotomy); FHNO (Femoral Head and Neck 97
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Ostectomy)
Breed (n)
Age (month) BM (kg) SCL (cm) Type of surgery
ASA Category (n)
Group D (n = 22)
Group C (n = 17)
p-Value
5 Mix breed 3 Labrador retriever 2 Pincher 2 German Shepherd 2 Dachshund 8 Other breed 48 (10−132) 26 (3–40) 70 (35–80) 8 TPLO 4 Osteosynthesis of a femoral fracture 4 FHNO 3 Medial patellar luxation repair 2 Hind limb amputation 1 Osteosynthesis of a tibial fracture ASA I (15) ASA II (7)
10 Mix breed 4 Labrador retriever 3 Other breed
Not evaluated
84 (11–168) 27 (3–40) 64 (30–80) 9 TPLO 3 FHNO 3 Medial patellar luxation repair 2 Osteosynthesis of a femoral fracture
0.10 0.66 0.90 Not evaluated
ASA I (12) ASA II (5)
0.92
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