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Analgesic effect of a single-dose of perineural dexamethasone on ultrasound-guided femoral nerve block after total knee replacement
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Rev Esp Anestesiol Reanim. 2016;xxx(xx):xxx---xxx
Revista Española de Anestesiología y Reanimación www.elsevier.es/redar
ORIGINAL ARTICLE
Analgesic effect of a single-dose of perineural dexamethasone on ultrasound-guided femoral nerve block after total knee replacement夽 C. Morales-Mu˜ noz ∗ , J.L. Sánchez-Ramos, M.D. Díaz-Lara, J. González-González, I. Gallego-Alonso, M.S. Hernández-del-Castillo Servicio de Anestesiología y Reanimación, Complejo Hospitalario Universitario Juan Ramón Jiménez, Huelva, Spain Received 27 December 2015; accepted 24 May 2016
KEYWORDS Dexamethasone; Femoral nerve block; Postoperative analgesia; Total knee replacement
Abstract Introduction: Total knee replacement is usually a very painful procedure. A single-dose of femoral nerve block has been shown to provide similar analgesia to an epidural, with fewer side effects, but limited in time. Objective: To compare the analgesia provided by dexamethasone used at perineural level in the femoral nerve block after total knee replacement with the one used at intravenous level, and with that of a control group. Material and methods: A prospective, randomised, double-blind controlled trial was conducted on 81 patients randomly assigned to one of three groups: (1) IV dexamethasone (8 mg); (2) perineural dexamethasone (8 mg), and (3) placebo. All patients received 20 ml of ropivacaine 0.5% for femoral nerve block. The primary outcome was the duration of the sensory-analgesic block of the femoral nerve block. The secondary outcomes included pain intensity measurements, patient satisfaction, and incidence of complications. Results: Randomisation was effective. Analgesia duration was significantly higher (P < .0001) in the perineural dexamethasone group (mean 1152.2 min, 95% confidence interval [95% CI]: 756.9---1547.6) in comparison with the control group (mean 186 min, 95% CI: 81.2---292) and dexamethasone IV group (mean 159.4 min, 95% CI: 109.8---209). Postoperative pain, complications and side effects were also lower in this group. Conclusions: Dexamethasone prolongs sensory block of single dose of femoral nerve block using ropivacaine. It also provides better analgesia and patient satisfaction, with fewer side effects. © 2016 Sociedad Espa˜ nola de Anestesiolog´ıa, Reanimaci´ on y Terap´ eutica del Dolor. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
夽 Please cite this article as: Morales-Mu˜ noz C, Sánchez-Ramos JL, Díaz-Lara MD, González-González J, Gallego-Alonso I, Hernández-delCastillo MS. Eficacia analgésica de una dosis única de dexametasona perineural en el bloqueo ecoguiado del nervio femoral en cirugía de prótesis total de rodilla. Rev Esp Anestesiol Reanim. 2016. http://dx.doi.org/10.1016/j.redar.2016.05.006 ∗ Corresponding author. noz). E-mail address: [email protected] (C. Morales-Mu˜
2341-1929/© 2016 Sociedad Espa˜ nola de Anestesiolog´ıa, Reanimaci´ on y Terap´ eutica del Dolor. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
REDARE-719; No. of Pages 8
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PALABRAS CLAVE Dexametasona; Bloqueo femoral; Analgesia postoperatoria; Cirugía de prótesis de rodilla
Eficacia analgésica de una dosis única de dexametasona perineural en el bloqueo ecoguiado del nervio femoral en cirugía de prótesis total de rodilla Resumen Introducción: La cirugía de prótesis de rodilla se caracteriza por tener un postoperatorio muy doloroso. El bloqueo del nervio femoral a dosis única ha demostrado proporcionar una analgesia similar a la epidural, con menos efectos secundarios pero limitado en el tiempo. Objetivo: Evaluar la eficacia de la analgesia proporcionada por la dexametasona utilizada a nivel perineural en el bloqueo del nervio femoral para cirugía de prótesis de rodilla, comparada con la aplicada a nivel intravenoso y con un grupo control. Material y métodos: Estudio prospectivo, aleatorizado, con enmascaramiento doble, controlado. Un total de 81 pacientes fueron aleatoriamente divididos en 3 grupos de estudio: (1) dexametasona 8 mg i.v.; (2) dexametasona 8 mg perineural, y (3) placebo. Todos los pacientes recibieron un bloqueo femoral con 20 ml de ropivacaína al 0,5%. La variable principal fue la duración del bloqueo sensitivo-analgésico del nervio femoral. Como variables secundarias se midieron el dolor según EVA, la satisfacción del paciente y la incidencia de complicaciones. Resultados: La aleatorización fue efectiva. La duración de la analgesia fue significativamente mayor (p < 0,0001) en el grupo dexametasona perineural (1.152,2 min; IC 95%: 756,9---1.547,6) comparada con el grupo control (186 min; IC 95%: 81,2---292) y el grupo dexametasona i.v. (159,4 min; IC 95%: 109,8---209). El dolor postoperatorio, la incidencia de complicaciones y los efectos secundarios también fueron menores en este grupo. Conclusiones: La dexametasona prolonga el bloqueo sensitivo del nervio femoral realizado con ropivacaína, a la vez que proporciona una mejor analgesia con menos efectos secundarios. © 2016 Sociedad Espa˜ nola de Anestesiolog´ıa, Reanimaci´ on y Terap´ eutica del Dolor. Publicado por Elsevier Espa˜ na, S.L.U. Todos los derechos reservados.
Introduction
Materials and methods
Total knee arthroplasty is characterised by substantial postoperative pain.1 Single dose femoral nerve block has been shown to be useful and effective2,3 in controlling postoperative pain, although duration of a analgesia is limited. Several studies have sought to prolong the duration of locoregional nerve blockade with local anaesthetic (LA) coadjuvants,4 such as adrenaline, opioids, ketamine or midazolam, although the analgesic effect has been limited. Alpha 2 adrenergic receptor agonists (clonidine5 and dexmedetomidine6 ) have been shown to significantly prolong analgesic effect, but are associated with serious adverse effects. Dexamethasone, however, prolongs the duration of analgesia in brachial plexus7---15 and sciatic16,17 nerve blocks, with no side effects. Research suggests that this is because dexamethasone attenuates surgery-induced inflammation by suppressing ectopic neural discharge and potentiating the activity of inhibitory potassium channels on nociceptive C-fibres,18---20 on the one hand, and by exerting a vasoconstrictive effect21 that slows down LA absorption, on the other. No studies have yet evaluated perineural (PN) administration of dexamethasone for femoral nerve block. The aim of this study has been to evaluate the efficacy and safety of PN vs IV dexamethasone compared with controls in femoral nerve block for knee replacement surgery.
The study was approved by the ethics committee of the Complejo Hospitalario Universitario de Huelva Juan Ramón Jiménez, authorising the use of PN dexamethasone. Informed written consent was obtained from 81 patients scheduled for knee replacement surgery who voluntarily agreed to take part in the study. Patients were randomised to receive single-dose postoperative femoral nerve block using one of the following drug combinations: (1) IV Dex group: PN administration of 20 ml of 0.5% ropivacaine with 2 ml saline solution (SS) and 2 ml (8 mg) IV dexamethasone; (2) PN Dex group: PN administration of 20 ml of 0.5% ropivacaine with 2 ml (8 mg) dexamethasone and 2 ml IV SS; (3) Control Group: PN administration of 20 ml of 0.5% ropivacaine with 2 ml SS and 2 ml IV SS. Computer software was used to randomise subjects into blocks corresponding to the study groups. The allocation of each patient to a particular group and drug treatment was placed in sealed envelopes, numbered sequentially from 1 to 81. Inclusion criteria were: patients scheduled for knee replacement surgery under spinal anaesthesia (10---12 mg hyperbaric bupivacaine and 10 g fentanyl using a 24G Sprotte cannula [Pajunk® , Germany]). Exclusion criteria were: sensitivity to or intolerance of study LAs, morphine or morphine derivatives, diabetes, peripheral nerve damage and prior treatment with steroids for over 6 months. The following
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Analgesic effect of a single-dose of perineural dexamethasone on ultrasound variables were also recorded: demographic (age, sex, body mass index [BMI]), clinical (comorbidities, American Society of Anesthesiologists [ASA] status), and technical (type of prosthesis, surgeon, ischaemia time, quality of blockade [good/bad ultrasound vision, positive/negative quadriceps response the neurostimulation]) characteristics. The operating room anaesthesiologist was in charge of preparing the drug combination (according to group allocation), which was then given to the post-anaesthesia care unit (PACU) anaesthesiologist, who was responsible for performing the nerve block and prescribing postoperative analgesia. All nerve blocks were performed by highly experienced anaesthesiologists using a combination of direct ultrasound vision (MyLab 25 Gold, Esaote® , Genoa, Italy) and neurostimulation. Nerve block was performed using a high-frequency (8---12 MHz) linear probe to locate the femoral vein and artery in the inguinal region. The femoral nerve is a hyperechoic, triangular-shaped structure immediately lateral to the femoral nerve. The block was performed in plane (long axis), with the tip of the needle in view at all times to place it adjacent to the lateral surface of the femoral artery. A 22G, 50---80 mm (depending on the depth of the nerve) Uniplex® (UniPlex NanoLine, Pajunk® , Germany) cannula was used. Correct localisation of the nerve in confirmed by the presence of a positive femoral motor response (quadriceps contraction with a low-intensity stimulus of 0.5 mA, 2 Hz for less than 0.1 ms). LA was infused under direct ultrasound vision to ensure even distribution around the femoral nerve. The blockade was performed when the effect of the motor block was partially reversed (Bromage 3: able to move knees) and patients reported no pain in the operated limb. Postoperative analgesia for the first 48 h consisted of continuous perfusion of metamizol (5 mg min−1 ) and ondansetron (16 g min−1 ) together with 3 mg boluses of morphine delivered intermittently using a PCA CADD patient-controlled infusion pump (Smiths Medical® , Kent, UK) with a 15 min lock-out interval. Patients were evaluated on discharge from the PACU, and at 24 and 48 h by an anaesthesiologist blinded to group allocation. The primary study variable was duration of femoral nerve analgesia, defined as the time from administration of the block to the first demand for rescue analgesia using the PCA system. Patients were instructed to start using the PCA as soon as they experienced moderate pain in the operated limb. Secondary variables were: pain intensity measured on a visual analogues scale (VAS); consumption of morphine, measured in milligrams on the PCA system; patient satisfaction with the assigned analgesia technique, rated from 1 to 4 (1: very satisfied; 2: satisfied; 3: dissatisfied; 4: extremely dissatisfied). For the purpose of statistical analysis, these scores were later grouped as very satisfied (1 and 2), and not satisfied (3 and 4); quality of sleep, rated from 0 to 2 (0: good sleep; 1: interrupted sleep; 2: no sleep at all). For the purpose of statistical analysis, these scores were later grouped as good sleep (0) and poor sleep (1 and 2); time to recovery (defined as the time from the end of surgery to hospital discharge); motor and sensory block at 24 and 48 h; motor block, rated from 1 to 3 according to the patient’s ability to flex the operated limb (1: normal movement; 2: limited movement; 3: no movement); sensation in the leg, rated from 1 to 3 according to the patient’s sensitivity to a pin prick on the inside of the leg, above and below the knee
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(1: normal sensation; 2: limited sensation; 3: no sensation); onset of side effects or complications, specifically, nausea, vomiting or itching in the first 24---48 h, and nerve damage, infection and hyperglycaemia.
Statistical analysis Demographic and clinical variables were first analysed using univariate descriptive techniques. Once the variables had been categorised, a bivariate descriptive analysis was performed. Quantitative variables were compared between groups using analysis of variance (ANOVA). Graphic techniques (de-trended QQ plots) were used to verify normality and Levene’s test was used to verify homogeneity of variance. Welch’s t-test was used for unequal variances. The Kruskal---Wallis nonparametric test was used to analyse variables with a non-normal distribution. The chi-squared test was used to analyse correlations between qualitative variables. The effect of each study treatment was estimated by calculating the differences in quantitative parameters (means and percentages) among the 3 groups. Significance was set at 5% for all statistical tests. The statistical analysis was performed on SPSS, version 20. The general linear model repeated measures analysis in SPSS was performed to avoid problems related with repeated comparison of correlated variables, to control the effect of multiple comparisons, and to observe possible differences in trends among the 3 study groups. This model was used to analyse differences in repeat measures of quantitative variables (pain measured on the VAS scale and consumption of morphine).
Sample size Sample size was calculated on the basis of similar studies on lower limb orthopaedic surgery comparing the duration of brachial plexus block (interscalene approach) with long-acting LA with and without coadjuvant dexamethasone. Cummings et al.8 observed longer lasting analgesia in the dexamethasone (1488 min; dt = 864 min) vs the no dexamethasone group (888 min; dt = 564 min). On the basis of these findings, and for a confidence interval of 95% and a power of 80%, we estimated that at least 48 patients divided into 2 equal size groups (24 in each) would be needed to obtain a sample capable of showing similar inter-group differences. A 10% margin was added to compensate for potential dropouts over the study period, bringing the total needed in each group to 27. A third group was formed to monitor the effect of IV dexamethasone in this type of surgery. Thus, the study comprised 3 groups of 27 patients per group (81 patients).
Results Patients were recruited between May 2014 and July 2015, following the flow chart shown in Fig. 1. Demographic, preoperative and intraoperative characteristics and surgical techniques were similar in all groups, showing that randomisation was effective (Table 1). In patients not requiring rescue analgesia due to the effectiveness of the block, the duration of femoral block was taken to be 48 h, this being the observation period of the primary variable.
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C. Morales-Mu˜ noz et al. Evaluated for inclusion (n=126)
Recruitment
Excluded (n=45) Did not meet inclusion criteria (n=30) Refused to participate (n=11) Did not understand the PCA (n=4)
Randomised (n=81)
IV Dexamethasone (n=27)
PN Dexamethasone (n=27)
Control (n=27)
No patients were lost during the first 48 postoperative hours
Analysed (n=27)
Analysed (n=27)
Figure 1
Table 1
Analysed (n=27)
Allocation
Follow-up
Analysis
CONSORT flowchart.
Demographic, clinical and technical characteristics of patients, by groups.
Characteristics
Classification
IV dexamethasone
PN dexamethasone
Controls
p
Age (years) BMI Sex
Median (95% CI) Median (95% CI) Female Male II III
68.8 (65.3---72.2) 31.1 (29.6---32.7) 19 (70.4%) 8 (29.6%) 23 (85.2%) 4 (14.8%)
70.5 (67.8---73.1) 31.7 (30---33.5) 18 (66.7%) 9 (33.3%) 16 (59.3%) 11 (40.7%)
68.8 (65.3---72.6) 30.2 (28.3---32.1) 21 (77.8%) 6 (22.2%) 21 (77.8%) 6 (22.2%)
0.234 0.458 0.654
19 (70.3%) 11 (40.7%) 16 (59.2%) 3 (11.1%) 2 (7.4%) 3 (11.1%)
21 (77.8%) 11 (40.7%) 17 (63%) 1 (3.7%) 1 (3.7%) 6 (22%)
14 (51.8%) 12 (44.4%) 12 (44.4%) 7 (25.9%) 1 (3.7%) 3 (11.1%)
13 (48.2%) 6 (22.2%) 8 (29.6%) 11 (40.7%) 9 (33.4%) 4 (14.8%) 3 (11.1%) 55 (51---59) 26 (96.3%) 1 (3.7%) 25 (92.6%) 2 (7.4%) 0
10 (37%) 8 (29.6%) 9 (33.4%) 12 (44.4%) 8 (29.6%) 4 (14.8%) 3 (11.1%) 55 (51---59) 27 (100%) 0 (0%) 23 (85.2%) 4 (14.8%) 0
10 (37%) 8 (29.6%) 9 (33.4%) 11 (40.7%) 9 (33.4%) 5 (18.5%) 2 (7.4%) 51 (47---55) 25 (92.6%) 2 (7.4%) 25 (92.6%) 2 (7.4%) 0
ASA class Comorbidities HTN Dyslipidaemia Obesity Asthma Hypothyroidism COPD Type of surgery
Surgeon
Ischaemia time (min) Quality of ultrasound view Response to neurostimulation Failed block
0.082 NS
Triathlon Vanguard Others Surgeon 1 Surgeon 2 Surgeon 3 Others Median (95% CI) Good Poor Good Poor
NS
NS
0.197 0.354 0.574 NS
ASA: American Society of Anesthesiologists: BMI: body mass index; CI: confidence interval; COPD: chronic obstructive pulmonary disease; HTN: arterial hypertension; IB: intravenous; min: minutes; n: number; NS: no significance; PN: perineural. Data are shown as mean plus 95% confidence interval and number plus percentage.
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Analgesic effect of a single-dose of perineural dexamethasone on ultrasound 1800 1600 1400 1200 1000
IV Dex
800
PN Dex Control
600 400 200 0
Duration analgesia (min)
Figure 2
Duration of femoral block analgesia, by groups.
PN dexamethasone significantly prolonged (p < 0.00001) duration of analgesia provided by the single 0.5% dose ropivacaine femoral nerve block (Fig. 2), Prolongation of the duration of the blockade was clinically significant with respect to both the control group (965.6 min; 95% CI: 676---1255.6) and the IV Dex group (992.8 min; 95% CI: 647.2---1338.6). Improved analgesia quality was accompanied by a lower VAS pain score (Fig. 3) at 24 h post surgery in the PN Dex group (1.9; 95% CI: 1.2---2.6), compared to the VAS score in the IV Dex group (4.8; 95% CI: 4.1---5.5) and in the control group (6; 95% CI: 5.1---6.8) (p < 0.00001). Similar VAS scores were recorded at 48 h post surgery (p < 0.0001), these being 2.4 (95% CI: 1.8---3) in the PN Dex group, 4.4 (95% CI: 3.8---5) in the IV Dex group, and 5.1 (95% CI: 4.3---5.9) in the control group. VAS pain intensity scores clearly differed between groups, and increase far less in the PN Dex group 10 9 8 7 6 5 4
IV Dex
3
PN Dex Control
2 1 0 VAS 24 h
Figure 3
VAS 48 h
VAS pain score at 24 and 48 h, by groups.
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compared to an increase of similar magnitude in both the IV Dex and control groups. In line with the foregoing results, morphine consumption was lower (p < 0.0001) in the PN Dex group at both 24 (8.3 mg; 95% CI: 3.9---12.7) and 48 h (13.3 mg; 95% CI: 7.8---18.6) vs the other 2 study groups (Table 2). Increase in morphine consumption also differed among groups, with a far smaller increase in the PN Dex group compared with the IV Dex and control groups, where a far greater increase was observed. Sleep quality in the first 24 h was better in the PN Dex group, in which 74.1% of patients reported enjoying a good night’s sleep compared with 33.3% in the IV Dex group and 29.6% in controls (p < 0.0001). Similar values were observed at 48 h: in the PN Dex group, 63% reported a good night’s sleep, vs 29.6% in the IV Dex group and 37% in the control group (p < 0.034). Patient satisfaction was also higher in the PN Dex group: 66.7% were very satisfied compared with 48.1% in the IV Dex group, and 29.6% in the control group (p < 0.025). Time to recovery was similar in all groups (p > 0.2): PN Dex 4.6 days (95% CI: 4.2---5.1), IV Dex 4.3 days (95% CI: 4---4.6), controls 4.7 days (95% CI: 4.1---5.3). In terms of complications, none of the study patients presented paraesthesia, numbness or weakness in the operated limb at the time of discharge, and no cases of injection site haematoma or infection were observed. However, a high rate of postoperative nausea and vomiting was observed in the control group (44.4%) compared with the IV Dex (11.1%) and PN Dex (3.7%) groups (p < 0.0001). Hyperglycaemia was more common in the IV Dex group, although this was not statistically significant. No differences among groups were observed in terms of sensory/motor block of the operated limb at 24 and 48 h post surgery.
Discussion In the management of postoperative pain following knee surgery, our results show that dexamethasone significantly prolongs the duration of the analgesic effect of femoral nerve block with single dose ropivacaine. This finding is consistent with that of other studies evaluating brachial plexus block in upper limb surgery.7---15 However, direct comparisons should be approached with caution due to the extreme heterogeneity of these studies (different sample size, nerve block type and technique used, volume and concentration of LA administered, PN dexamethasone dose used, presence of an additional coadjuvant [clonidine, ephedrine], and inclusion of a control group or an IV dexamethasone group). The prolonged analgesia observed in our sample (on average between 11 and 21 h) are in line with the results reported by Choi et al.7 in their review of 9 studies in upper limb nerve blocks. In this case, the authors found that dexamethasone prolonged the effect of long-acting LA infusion (ropivacaine/bupivacaine) by 576 min. Albrecht et al.,22 in their 2015 analysis of 29 studies in upper limb, sciatic, ankle, peribullar, tranversus abdominis and oral nerve blocks, found that dexamethasone prolonged the effect of long-acting LA by 488 min. The good results obtained in our sample could be due to 2 factors: accurate administration of the blockade, using both ultrasound and neurostimulation to guide placement to achieve a 100% success rate; and the use of ropivacaine, as studies have shown that coadjuvant
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C. Morales-Mu˜ noz et al. Table 2
Summary of findings. IV dexamethasone
PN dexamethasone
Controls
p
Morphine consumption 24 h (mg) Morphine consumption 48 h (mg)
26.3 (18.4---34.2) 43.8 (32.7---54.8)
8.3 (3.9---12.7) 13.3 (7.8---18.6)
26.3 (18.7---33.8) 46.4 (34---58.7)
0.0001 0.0001
Quality of sleep 24 h Good Poor
9 (33.3%) 18 (66.7%)
20 (74.1%) 7 (25.9%)
8 (29.6%) 19 (70.4%)
Quality of sleep 48 h Good Poor
8 (29.6%) 19 (70.4%)
17 (63%) 10 (37%)
10 (37%) 17 (63%)
Patient satisfaction Very satisfied Dissatisfied
13 (48.1%) 14 (51.9%)
18 (66.7%) 9 (33.3%)
8 (29.6%) 19 (70.4%)
Motor block 24 h Normal Limited
23 (85.2%) 4 (14.8%)
21 (77.8%) 6 (22.2%)
25 (92.6%) 2 (7.4%)
Motor block 48 h Normal Limited
26 (96.3%) 1 (3.7%)
25 (92.6%) 2 (7.4%)
25 (92.6%) 2 (7.4%)
Sensory block 24 h Normal Limited
25 (92.6%) 2 (7.4%)
21 (77.8%) 6 (22.2%)
25 (92.6%) 2 (7.4%)
Sensory block 48 h Normal Limited
27 (100%) 0
26 (96.3%) 1 (3.7%)
26 (96.3%) 1 (3.7%)
Complications Nausea/vomiting Hyperglycaemia Nerve damage Infection Others Time to recovery (days)
3 (11.1%) 3 (11.1%) 0 1 (3.7%) 3 (11.1%) 4.3 (4---4.6)
1 (3.7%) 0 0 0 2 (7.4%) 4.6 (4.2---5.1)
12 (44.4%) 1 (3.7%) 0 2 (7.4%) 5 (18.5%) 4.7 (4.1---5.3)
0.001
0.034
0.025
NS
NS
NS
NS
0.0001 NS --NS NS 0.20
CI: confidence interval; h: hours; IV: intravenous; mg: milligrams; NS: no significance; PN: perineural. Data are shown as mean plus 95% confidence interval and number plus percentage.
dexamethasone give better results with this LA than with bupivacaine.8 The significantly lower VAS score observed in the PN Dex group is evidence of the prolonged analgesia provided by femoral block with dexamethasone, which was accompanied by a decreased sensation of pain at 24 and 48 h post surgery. Most studies13,17,21,22 have so far reported lower VAS scores at 24 h, but not at 48 h, at which time point scores are similar among groups. The difference in our findings could be due to the far greater prolongation of femoral block analgesia achieved in our patients compared to earlier studies. It is also interesting to note that better VAS scores at both 24 and 48 h post surgery were obtained in the IV Dex group compared with controls, which we believe could be due to the anti-inflammatory effect of IV dexamethasone. In parallel with the foregoing findings, the PN Dex group showed lower morphine consumption at 24 and 48 h post surgery and a lower rate of postoperative nausea and vomiting, better quality of sleep in the first 24 and 48 h, and greater satisfaction with the technique used. Yet again, these findings
contrast with those reported in the most important studies reviewed,13,21,22 in which longer analgesic effect did not correlate with greater satisfaction or lower morphine consumption. We believe that the prolongation of the analgesic effect obtained with LA and coadjuvant dexamethasone would explain these differences. Although these improved results would be expected to result in a speedier recovery and shorter hospital stay in the PN Dex group, this was in fact not the case. We believe this is due to the fact that postoperative recovery depends on various factors, including the type of surgery and the demographic and clinical characteristics of the patient. Although pain management is important, it is not essential to the recovery process, and considering the demographic and clinical characteristics of our sample (average age of between 68 and 70 years, with a high BMI and considerable comorbidity [ASA II/III]), it is clear that good pain management alone would not be enough to shorten the hospital stay. The exact mechanism of action with which dexamethasone prolongs the analgesic effect of LAs is unknown,
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Analgesic effect of a single-dose of perineural dexamethasone on ultrasound although several hypotheses have been put forward. It has been suggested that the vasoconstrictive action of the drug could delay PN absorption and elimination of LA.18 Some studies, however, claim that dexamethasone attenuates surgery-induced inflammation by suppressing ectopic neural discharge and potentiating the activity of inhibitory potassium channels on nociceptive C-fibres.19 Finally, some authors attribute the analgesic effect of the drug to its systemic anti-inflammatory action. PN administration of dexamethasone is a safe procedure: no cases of dexamethasone-induced neurotoxicity or hyperalgesia were observed in the first 48 h post administration in the 27 cases included in the PN Dex group. Although the use of dexamethasone remains controversial, and concerns have been raised about its off-label use as a coadjuvant in regional nerve block, there is no clear evidence in human trials of neurotoxicity associated with the drug. However, studies in animals suggest a certain level of toxicity when dexamethasone concentration is increased from 66 to 133 g/ml and the drug is used in combination with ropivacaine.23 In our study, dexamethasone was administered at a dose of 400 g/ml, which, in proportion to average weight, is far lower (1.71 g/ml) than the dose determined to be dangerous by Williams et al.23 Recent studies have suggested that nerve damage following spinal administration of steroids is due to particle size, insofar as larger particles can occlude blood vessels and reduce medullary blood flow. Comparing the size of the particles of various steroids, Benzon et al.24 observed that dexamethasone sodium phosphate (used in our study) is a pure liquid steroid with no particles, and could therefore be safer and more effective than other steroids used in connection with nerve block techniques. An analysis of the complication arising from the anaesthetic technique showed no evidence of neurological complications in any study group. According to Brull et al.,25 the risk of nerve damage following peripheral nerve block is estimated to be 0.34%; our sample, therefore, would have been large enough to reveal neurological complications derived from the technique and from the PN administration of dexamethasone. Differences in the incidence of hyperglycaemia at 24 h post surgery were not statistically significant, although a slight trend towards a higher incidence was observed in the IV Dex group. This suggests that administration of PN dexamethasone is safe in diabetic patients, although this hypothesis must be confirmed by specific tolerance studies in this patient population.26 Our study has some limitations. We would point out that as the knee is innervated anteriorly by branches of the femoral nerve, posteriorly by the sciatic nerve, and medially by the obturator nerve, we might have overlooked some major contributors to postoperative pain. Based on the low VAS scores obtained from the PN Dex group and the observations made by Chan et al.,4 we believe the involvement of the sciatic and obturator nerves to be minimal. Nevertheless, further studies combining different nerve blocks with dexamethasone would show whether analgesia is improved by blocking all 3 nerves supplying the knee. We encountered some difficulty in conducting a neurological examination of the operated knee in the immediate postoperative period because the limb was bandaged up to the groin in all patients, and some patients were instructed by the orthopaedic surgeon not to flex the knee for 24 h. This
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made is particularly difficult to accurately evaluate the level of sensory-motor blockade. However, we observed no significant inter-group differences in sensory and motor blockade of the operated limb. Another limitation to our study is the time limit (48 h) for collecting data relating to the primary variables. This prevented us from ascertaining whether VAS scores evened out over time in the 3 groups, or whether some patients presented hyperalgesia or chronic pain. Further studies with longer follow-up and monitoring periods are needed to explore the possibility of these complications presenting in the long-term. The optimal dexamethasone dose for PN administration has yet to be determined. Recent studies27,28 have shown that small doses (4---5 mg) are as effective as high doses (8 mg), leading us to suggest that further studies in low-dose dexamethasone are needed to determine the optimal dose for PN administration. In conclusion, we have shown that PN dexamethasone (8 mg) prolongs the duration of femoral nerve block with 0.5% ropivacaine. It also reduces the sensation of pain and improves quality of sleep in the first 24 and 48 h post surgery, reduces morphine consumption and incidence of adverse effects (nausea and vomiting) in the first 48 h after surgery. This is the first study to compare PN administration of dexamethasone in the context of femoral nerve block in knee replacement surgery in 2 study populations plus a control group. PN dexamethasone has been shown to be safe, with no evidence of neurotoxicity, hyperalgesia or hyperglycaemia in the immediate postoperative period.
Ethical responsibilities Protection of human and animal rights. The authors declare that the procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation and with those of the World Health Organisation and the Helsinki Declaration. Data confidentiality. The authors declare that they have followed the protocols implemented in their place of work regarding the use of patient data in publications. Right to privacy and informed consent. The authors have obtained the informed consent of all patients and/or subjects included in this manuscript. The informed consent forms can be obtained from the author for correspondence.
Conflict of interest The authors have no conflict of interest to declare.
References 1. Horlocker TT. Pain management in total joint arthroplasty: a historical review. Orthopedics. 2010;33:14---9. 2. Wu JWS, Wong YC. Elective unilateral total knee replacement using continuous femoral nerve blockade versus conventional patient-controlled analgesia: perioperative patient management based on a multidisciplinary pathway. Hong Kong Med J. 2014;20:45---51.
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8 3. Fischer HB, Simanski CJ, Sharp C, Bonnet F, Camu F, Neugebauer EA, et al. A procedure-specific systematic review and consensus recommendations for postoperative analgesia following total knee arthroplasty. Anaesthesia. 2008;63:1105---23. 4. Chan E-Y, Fransen M, Parker DA, Assam PN, Chua N. Femoral nerve blocks for acute postoperative pain after knee replacement surgery. Cochrane Database Syst Rev. 2014;5:CD009941. 5. Pöpping DM, Elia N, Marret E, Wenk M, Tramèr MR. Clonidine as an adjuvant to local anesthetics for peripheral nerve and plexus blocks: a meta-analysis of randomized trials. Anesthesiology. 2009;111:406---15. 6. Abdallah FW, Brull R. Facilitatory effects of perineural dexmedetomidine on neuraxial and peripheral nerve block: a systematic review and meta-analysis. Br J Anaesth. 2013;110:915---25. 7. Choi S, Rodseth R, McCartney CJL. Effects of dexamethasone as a local anaesthetic adjuvant for brachial plexus block: a systematic review and meta-analysis of randomized trials. Br J Anaesth. 2014;112:427---39. 8. Cummings KC, Napierkowski DE, Parra-Sanchez I, Kurz A, Dalton JE, Brems JJSD. Effect of dexamethasone on the duration of interscalene nerve blocks with ropivacaine or bupivacaine. Br J Anaesth. 2011;107:446---53. 9. Movafegh A, Razazian M, Hajimaohamadi F, Meysamie A. Dexamethasone added to lidocaine prolongs axillary brachial plexus blockade. Anesth Analg. 2006;102:263---7. 10. Parrington SJ, O’Donnell D, Chan VWS, Brown-Shreves D, Subramanyam R, Qu M, et al. Dexamethasone added to mepivacaine prolongs the duration of analgesia after supraclavicular brachial plexus blockade. Reg Anesth Pain Med. 2010;35: 422---6. 11. Tandoc MN, Fan L, Kolesnikov S, Kruglov A, Nader ND. Adjuvant dexamethasone with bupivacaine prolongs the duration of interscalene block: a prospective randomized trial. J Anesth. 2011;25:704---9. 12. Vieira P, Pulai I, Tsao GC, Manikantan P, Keller B, Connelly NR. Dexamethasone with bupivacaine increases duration of analgesia in ultrasound-guided interscalene brachial plexus blockade. Eur J Anaesthesiol. 2010;27:285---8. 13. Desmet M, Braems H, Reynvoet M, Plasschaert S, Van Cauwelaert J, Pottel H, et al. I.V. and perineural dexamethasone are equivalent in increasing the analgesic duration of a singleshot interscalene block with ropivacaine for shoulder surgery: a prospective, randomized, placebo-controlled study. Br J Anaesth. 2013;111:445---52. 14. Golwala MP, Swadia VN, Dhimar AA. Pain relief by dexamethasone as an adjuvant to local anaesthetics in supraclavicular brachial plexus block. J Anaesthesiol Clin Pharmacol. 2009;25:285---8. 15. Kim YJ, Lee GY, Kim DY, Kim CH, Baik H-J, Heo S. Dexamathasone added to levobupivacaine improves postoperative
C. Morales-Mu˜ noz et al.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
analgesia in ultrasound guided interscalene brachial plexus blockade for arthroscopic shoulder surgery. Korean J Anesthesiol. 2012;62:130---4. Rahangdale R, Kendall MC, McCarthy RJ, Tureanu L, Doty R Jr, Weingart A, et al. The effects of perineural versus intravenous dexamethasone on sciatic nerve blockade outcomes: a randomized, double-blind, placebo-controlled study. Anesth Analg. 2014;118:1113---9. Fredrickson Fanzca MJ, Danesh-Clough TK, White R. Adjuvant dexamethasone for bupivacaine sciatic and ankle blocks: results from 2 randomized placebo-controlled trials. Reg Anesth Pain Med. 2013;38:300---7. Attardi B, Takimoto K, Gealy R, Severns C, Levitan ES. Glucocorticoid induced up-regulation of a pituitary K+ channel mRNA in vitro and in vivo. Recept Channels. 1993;1:287---93. Johansson A, Hao J, Sjölund B. Local corticosteroid application blocks transmission in normal nociceptive C-fibres. Acta Anaesthesiol Scand. 1990;34:335---8. Ma R, Wang X, Lu C, Li C, Cheng Y, Ding G, et al. Dexamethasone attenuated bupivacaine-induced neuron injury in vitro through a threonine-serine protein kinase B-dependent mechanism. Neuroscience. 2010;167:329---42. Marks R, Barlow JW, Funder JW. Steroid-induced vasoconstriction: glucocorticoid antagonist studies. J Clin Endocrinol Metab. 1982;54:1075---7. Albrecht E, Kern C, Kirkham KR. A systematic review and metaanalysis of perineural dexamethasone for peripheral nerve blocks. Anaesthesia. 2015;70:71---83. Williams BA, Hough KA, Tsui BYK, Ibinson JW, Gold MS, Gebhart GF. Neurotoxicity of adjuvants used in perineural anesthesia and analgesia in comparison with ropivacaine. Reg Anesth Pain Med. 2011;36:225---30. Benzon HT, Chew T-L, McCarthy RJ, Benzon HA, Walega DR. Comparison of the particle sizes of different steroids and the effect of dilution: a review of the relative neurotoxicities of the steroids. Anesthesiology. 2007;106:331---8. Brull R, McCartney CJL, Chan VWS, el-Beheiry H. Neurological complications after regional anesthesia: contemporary estimates of risk. Anesth Analg. 2007;104:965---74. Williams Ba, Murinson BB, Grable BR, Orebaugh SL. Future considerations for pharmacologic adjuvants in single-injection peripheral nerve blocks for patients with diabetes mellitus. Reg Anesth Pain Med. 2009;34:445---57. Persec J, Persec Z, Kopljar M, Zupcic M, Sakic L, Zrinjscak IK, et al. Low-dose dexamethasone with levobupivacaine improves analgesia after supraclavicular brachial plexus blockade. Int Orthop. 2014;38:101---5. Knezevic NN, Anantamongkol U, Candido KD. Perineural dexamethasone added to local anesthesia for brachial plexus block improves pain but delays block onset and motor blockade recovery. Pain Phys. 2015;18:1---14.
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Revista Española de Anestesiología y Reanimación www.elsevier.es/redar
ORIGINAL ARTICLE
Analgesic effect of a single-dose of perineural dexamethasone on ultrasound-guided femoral nerve block after total knee replacement夽 C. Morales-Mu˜ noz ∗ , J.L. Sánchez-Ramos, M.D. Díaz-Lara, J. González-González, I. Gallego-Alonso, M.S. Hernández-del-Castillo Servicio de Anestesiología y Reanimación, Complejo Hospitalario Universitario Juan Ramón Jiménez, Huelva, Spain Received 27 December 2015; accepted 24 May 2016
KEYWORDS Dexamethasone; Femoral nerve block; Postoperative analgesia; Total knee replacement
Abstract Introduction: Total knee replacement is usually a very painful procedure. A single-dose of femoral nerve block has been shown to provide similar analgesia to an epidural, with fewer side effects, but limited in time. Objective: To compare the analgesia provided by dexamethasone used at perineural level in the femoral nerve block after total knee replacement with the one used at intravenous level, and with that of a control group. Material and methods: A prospective, randomised, double-blind controlled trial was conducted on 81 patients randomly assigned to one of three groups: (1) IV dexamethasone (8 mg); (2) perineural dexamethasone (8 mg), and (3) placebo. All patients received 20 ml of ropivacaine 0.5% for femoral nerve block. The primary outcome was the duration of the sensory-analgesic block of the femoral nerve block. The secondary outcomes included pain intensity measurements, patient satisfaction, and incidence of complications. Results: Randomisation was effective. Analgesia duration was significantly higher (P < .0001) in the perineural dexamethasone group (mean 1152.2 min, 95% confidence interval [95% CI]: 756.9---1547.6) in comparison with the control group (mean 186 min, 95% CI: 81.2---292) and dexamethasone IV group (mean 159.4 min, 95% CI: 109.8---209). Postoperative pain, complications and side effects were also lower in this group. Conclusions: Dexamethasone prolongs sensory block of single dose of femoral nerve block using ropivacaine. It also provides better analgesia and patient satisfaction, with fewer side effects. © 2016 Sociedad Espa˜ nola de Anestesiolog´ıa, Reanimaci´ on y Terap´ eutica del Dolor. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
夽 Please cite this article as: Morales-Mu˜ noz C, Sánchez-Ramos JL, Díaz-Lara MD, González-González J, Gallego-Alonso I, Hernández-delCastillo MS. Eficacia analgésica de una dosis única de dexametasona perineural en el bloqueo ecoguiado del nervio femoral en cirugía de prótesis total de rodilla. Rev Esp Anestesiol Reanim. 2016. http://dx.doi.org/10.1016/j.redar.2016.05.006 ∗ Corresponding author. noz). E-mail address: [email protected] (C. Morales-Mu˜
2341-1929/© 2016 Sociedad Espa˜ nola de Anestesiolog´ıa, Reanimaci´ on y Terap´ eutica del Dolor. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
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PALABRAS CLAVE Dexametasona; Bloqueo femoral; Analgesia postoperatoria; Cirugía de prótesis de rodilla
Eficacia analgésica de una dosis única de dexametasona perineural en el bloqueo ecoguiado del nervio femoral en cirugía de prótesis total de rodilla Resumen Introducción: La cirugía de prótesis de rodilla se caracteriza por tener un postoperatorio muy doloroso. El bloqueo del nervio femoral a dosis única ha demostrado proporcionar una analgesia similar a la epidural, con menos efectos secundarios pero limitado en el tiempo. Objetivo: Evaluar la eficacia de la analgesia proporcionada por la dexametasona utilizada a nivel perineural en el bloqueo del nervio femoral para cirugía de prótesis de rodilla, comparada con la aplicada a nivel intravenoso y con un grupo control. Material y métodos: Estudio prospectivo, aleatorizado, con enmascaramiento doble, controlado. Un total de 81 pacientes fueron aleatoriamente divididos en 3 grupos de estudio: (1) dexametasona 8 mg i.v.; (2) dexametasona 8 mg perineural, y (3) placebo. Todos los pacientes recibieron un bloqueo femoral con 20 ml de ropivacaína al 0,5%. La variable principal fue la duración del bloqueo sensitivo-analgésico del nervio femoral. Como variables secundarias se midieron el dolor según EVA, la satisfacción del paciente y la incidencia de complicaciones. Resultados: La aleatorización fue efectiva. La duración de la analgesia fue significativamente mayor (p < 0,0001) en el grupo dexametasona perineural (1.152,2 min; IC 95%: 756,9---1.547,6) comparada con el grupo control (186 min; IC 95%: 81,2---292) y el grupo dexametasona i.v. (159,4 min; IC 95%: 109,8---209). El dolor postoperatorio, la incidencia de complicaciones y los efectos secundarios también fueron menores en este grupo. Conclusiones: La dexametasona prolonga el bloqueo sensitivo del nervio femoral realizado con ropivacaína, a la vez que proporciona una mejor analgesia con menos efectos secundarios. © 2016 Sociedad Espa˜ nola de Anestesiolog´ıa, Reanimaci´ on y Terap´ eutica del Dolor. Publicado por Elsevier Espa˜ na, S.L.U. Todos los derechos reservados.
Introduction
Materials and methods
Total knee arthroplasty is characterised by substantial postoperative pain.1 Single dose femoral nerve block has been shown to be useful and effective2,3 in controlling postoperative pain, although duration of a analgesia is limited. Several studies have sought to prolong the duration of locoregional nerve blockade with local anaesthetic (LA) coadjuvants,4 such as adrenaline, opioids, ketamine or midazolam, although the analgesic effect has been limited. Alpha 2 adrenergic receptor agonists (clonidine5 and dexmedetomidine6 ) have been shown to significantly prolong analgesic effect, but are associated with serious adverse effects. Dexamethasone, however, prolongs the duration of analgesia in brachial plexus7---15 and sciatic16,17 nerve blocks, with no side effects. Research suggests that this is because dexamethasone attenuates surgery-induced inflammation by suppressing ectopic neural discharge and potentiating the activity of inhibitory potassium channels on nociceptive C-fibres,18---20 on the one hand, and by exerting a vasoconstrictive effect21 that slows down LA absorption, on the other. No studies have yet evaluated perineural (PN) administration of dexamethasone for femoral nerve block. The aim of this study has been to evaluate the efficacy and safety of PN vs IV dexamethasone compared with controls in femoral nerve block for knee replacement surgery.
The study was approved by the ethics committee of the Complejo Hospitalario Universitario de Huelva Juan Ramón Jiménez, authorising the use of PN dexamethasone. Informed written consent was obtained from 81 patients scheduled for knee replacement surgery who voluntarily agreed to take part in the study. Patients were randomised to receive single-dose postoperative femoral nerve block using one of the following drug combinations: (1) IV Dex group: PN administration of 20 ml of 0.5% ropivacaine with 2 ml saline solution (SS) and 2 ml (8 mg) IV dexamethasone; (2) PN Dex group: PN administration of 20 ml of 0.5% ropivacaine with 2 ml (8 mg) dexamethasone and 2 ml IV SS; (3) Control Group: PN administration of 20 ml of 0.5% ropivacaine with 2 ml SS and 2 ml IV SS. Computer software was used to randomise subjects into blocks corresponding to the study groups. The allocation of each patient to a particular group and drug treatment was placed in sealed envelopes, numbered sequentially from 1 to 81. Inclusion criteria were: patients scheduled for knee replacement surgery under spinal anaesthesia (10---12 mg hyperbaric bupivacaine and 10 g fentanyl using a 24G Sprotte cannula [Pajunk® , Germany]). Exclusion criteria were: sensitivity to or intolerance of study LAs, morphine or morphine derivatives, diabetes, peripheral nerve damage and prior treatment with steroids for over 6 months. The following
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Analgesic effect of a single-dose of perineural dexamethasone on ultrasound variables were also recorded: demographic (age, sex, body mass index [BMI]), clinical (comorbidities, American Society of Anesthesiologists [ASA] status), and technical (type of prosthesis, surgeon, ischaemia time, quality of blockade [good/bad ultrasound vision, positive/negative quadriceps response the neurostimulation]) characteristics. The operating room anaesthesiologist was in charge of preparing the drug combination (according to group allocation), which was then given to the post-anaesthesia care unit (PACU) anaesthesiologist, who was responsible for performing the nerve block and prescribing postoperative analgesia. All nerve blocks were performed by highly experienced anaesthesiologists using a combination of direct ultrasound vision (MyLab 25 Gold, Esaote® , Genoa, Italy) and neurostimulation. Nerve block was performed using a high-frequency (8---12 MHz) linear probe to locate the femoral vein and artery in the inguinal region. The femoral nerve is a hyperechoic, triangular-shaped structure immediately lateral to the femoral nerve. The block was performed in plane (long axis), with the tip of the needle in view at all times to place it adjacent to the lateral surface of the femoral artery. A 22G, 50---80 mm (depending on the depth of the nerve) Uniplex® (UniPlex NanoLine, Pajunk® , Germany) cannula was used. Correct localisation of the nerve in confirmed by the presence of a positive femoral motor response (quadriceps contraction with a low-intensity stimulus of 0.5 mA, 2 Hz for less than 0.1 ms). LA was infused under direct ultrasound vision to ensure even distribution around the femoral nerve. The blockade was performed when the effect of the motor block was partially reversed (Bromage 3: able to move knees) and patients reported no pain in the operated limb. Postoperative analgesia for the first 48 h consisted of continuous perfusion of metamizol (5 mg min−1 ) and ondansetron (16 g min−1 ) together with 3 mg boluses of morphine delivered intermittently using a PCA CADD patient-controlled infusion pump (Smiths Medical® , Kent, UK) with a 15 min lock-out interval. Patients were evaluated on discharge from the PACU, and at 24 and 48 h by an anaesthesiologist blinded to group allocation. The primary study variable was duration of femoral nerve analgesia, defined as the time from administration of the block to the first demand for rescue analgesia using the PCA system. Patients were instructed to start using the PCA as soon as they experienced moderate pain in the operated limb. Secondary variables were: pain intensity measured on a visual analogues scale (VAS); consumption of morphine, measured in milligrams on the PCA system; patient satisfaction with the assigned analgesia technique, rated from 1 to 4 (1: very satisfied; 2: satisfied; 3: dissatisfied; 4: extremely dissatisfied). For the purpose of statistical analysis, these scores were later grouped as very satisfied (1 and 2), and not satisfied (3 and 4); quality of sleep, rated from 0 to 2 (0: good sleep; 1: interrupted sleep; 2: no sleep at all). For the purpose of statistical analysis, these scores were later grouped as good sleep (0) and poor sleep (1 and 2); time to recovery (defined as the time from the end of surgery to hospital discharge); motor and sensory block at 24 and 48 h; motor block, rated from 1 to 3 according to the patient’s ability to flex the operated limb (1: normal movement; 2: limited movement; 3: no movement); sensation in the leg, rated from 1 to 3 according to the patient’s sensitivity to a pin prick on the inside of the leg, above and below the knee
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(1: normal sensation; 2: limited sensation; 3: no sensation); onset of side effects or complications, specifically, nausea, vomiting or itching in the first 24---48 h, and nerve damage, infection and hyperglycaemia.
Statistical analysis Demographic and clinical variables were first analysed using univariate descriptive techniques. Once the variables had been categorised, a bivariate descriptive analysis was performed. Quantitative variables were compared between groups using analysis of variance (ANOVA). Graphic techniques (de-trended QQ plots) were used to verify normality and Levene’s test was used to verify homogeneity of variance. Welch’s t-test was used for unequal variances. The Kruskal---Wallis nonparametric test was used to analyse variables with a non-normal distribution. The chi-squared test was used to analyse correlations between qualitative variables. The effect of each study treatment was estimated by calculating the differences in quantitative parameters (means and percentages) among the 3 groups. Significance was set at 5% for all statistical tests. The statistical analysis was performed on SPSS, version 20. The general linear model repeated measures analysis in SPSS was performed to avoid problems related with repeated comparison of correlated variables, to control the effect of multiple comparisons, and to observe possible differences in trends among the 3 study groups. This model was used to analyse differences in repeat measures of quantitative variables (pain measured on the VAS scale and consumption of morphine).
Sample size Sample size was calculated on the basis of similar studies on lower limb orthopaedic surgery comparing the duration of brachial plexus block (interscalene approach) with long-acting LA with and without coadjuvant dexamethasone. Cummings et al.8 observed longer lasting analgesia in the dexamethasone (1488 min; dt = 864 min) vs the no dexamethasone group (888 min; dt = 564 min). On the basis of these findings, and for a confidence interval of 95% and a power of 80%, we estimated that at least 48 patients divided into 2 equal size groups (24 in each) would be needed to obtain a sample capable of showing similar inter-group differences. A 10% margin was added to compensate for potential dropouts over the study period, bringing the total needed in each group to 27. A third group was formed to monitor the effect of IV dexamethasone in this type of surgery. Thus, the study comprised 3 groups of 27 patients per group (81 patients).
Results Patients were recruited between May 2014 and July 2015, following the flow chart shown in Fig. 1. Demographic, preoperative and intraoperative characteristics and surgical techniques were similar in all groups, showing that randomisation was effective (Table 1). In patients not requiring rescue analgesia due to the effectiveness of the block, the duration of femoral block was taken to be 48 h, this being the observation period of the primary variable.
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C. Morales-Mu˜ noz et al. Evaluated for inclusion (n=126)
Recruitment
Excluded (n=45) Did not meet inclusion criteria (n=30) Refused to participate (n=11) Did not understand the PCA (n=4)
Randomised (n=81)
IV Dexamethasone (n=27)
PN Dexamethasone (n=27)
Control (n=27)
No patients were lost during the first 48 postoperative hours
Analysed (n=27)
Analysed (n=27)
Figure 1
Table 1
Analysed (n=27)
Allocation
Follow-up
Analysis
CONSORT flowchart.
Demographic, clinical and technical characteristics of patients, by groups.
Characteristics
Classification
IV dexamethasone
PN dexamethasone
Controls
p
Age (years) BMI Sex
Median (95% CI) Median (95% CI) Female Male II III
68.8 (65.3---72.2) 31.1 (29.6---32.7) 19 (70.4%) 8 (29.6%) 23 (85.2%) 4 (14.8%)
70.5 (67.8---73.1) 31.7 (30---33.5) 18 (66.7%) 9 (33.3%) 16 (59.3%) 11 (40.7%)
68.8 (65.3---72.6) 30.2 (28.3---32.1) 21 (77.8%) 6 (22.2%) 21 (77.8%) 6 (22.2%)
0.234 0.458 0.654
19 (70.3%) 11 (40.7%) 16 (59.2%) 3 (11.1%) 2 (7.4%) 3 (11.1%)
21 (77.8%) 11 (40.7%) 17 (63%) 1 (3.7%) 1 (3.7%) 6 (22%)
14 (51.8%) 12 (44.4%) 12 (44.4%) 7 (25.9%) 1 (3.7%) 3 (11.1%)
13 (48.2%) 6 (22.2%) 8 (29.6%) 11 (40.7%) 9 (33.4%) 4 (14.8%) 3 (11.1%) 55 (51---59) 26 (96.3%) 1 (3.7%) 25 (92.6%) 2 (7.4%) 0
10 (37%) 8 (29.6%) 9 (33.4%) 12 (44.4%) 8 (29.6%) 4 (14.8%) 3 (11.1%) 55 (51---59) 27 (100%) 0 (0%) 23 (85.2%) 4 (14.8%) 0
10 (37%) 8 (29.6%) 9 (33.4%) 11 (40.7%) 9 (33.4%) 5 (18.5%) 2 (7.4%) 51 (47---55) 25 (92.6%) 2 (7.4%) 25 (92.6%) 2 (7.4%) 0
ASA class Comorbidities HTN Dyslipidaemia Obesity Asthma Hypothyroidism COPD Type of surgery
Surgeon
Ischaemia time (min) Quality of ultrasound view Response to neurostimulation Failed block
0.082 NS
Triathlon Vanguard Others Surgeon 1 Surgeon 2 Surgeon 3 Others Median (95% CI) Good Poor Good Poor
NS
NS
0.197 0.354 0.574 NS
ASA: American Society of Anesthesiologists: BMI: body mass index; CI: confidence interval; COPD: chronic obstructive pulmonary disease; HTN: arterial hypertension; IB: intravenous; min: minutes; n: number; NS: no significance; PN: perineural. Data are shown as mean plus 95% confidence interval and number plus percentage.
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Analgesic effect of a single-dose of perineural dexamethasone on ultrasound 1800 1600 1400 1200 1000
IV Dex
800
PN Dex Control
600 400 200 0
Duration analgesia (min)
Figure 2
Duration of femoral block analgesia, by groups.
PN dexamethasone significantly prolonged (p < 0.00001) duration of analgesia provided by the single 0.5% dose ropivacaine femoral nerve block (Fig. 2), Prolongation of the duration of the blockade was clinically significant with respect to both the control group (965.6 min; 95% CI: 676---1255.6) and the IV Dex group (992.8 min; 95% CI: 647.2---1338.6). Improved analgesia quality was accompanied by a lower VAS pain score (Fig. 3) at 24 h post surgery in the PN Dex group (1.9; 95% CI: 1.2---2.6), compared to the VAS score in the IV Dex group (4.8; 95% CI: 4.1---5.5) and in the control group (6; 95% CI: 5.1---6.8) (p < 0.00001). Similar VAS scores were recorded at 48 h post surgery (p < 0.0001), these being 2.4 (95% CI: 1.8---3) in the PN Dex group, 4.4 (95% CI: 3.8---5) in the IV Dex group, and 5.1 (95% CI: 4.3---5.9) in the control group. VAS pain intensity scores clearly differed between groups, and increase far less in the PN Dex group 10 9 8 7 6 5 4
IV Dex
3
PN Dex Control
2 1 0 VAS 24 h
Figure 3
VAS 48 h
VAS pain score at 24 and 48 h, by groups.
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compared to an increase of similar magnitude in both the IV Dex and control groups. In line with the foregoing results, morphine consumption was lower (p < 0.0001) in the PN Dex group at both 24 (8.3 mg; 95% CI: 3.9---12.7) and 48 h (13.3 mg; 95% CI: 7.8---18.6) vs the other 2 study groups (Table 2). Increase in morphine consumption also differed among groups, with a far smaller increase in the PN Dex group compared with the IV Dex and control groups, where a far greater increase was observed. Sleep quality in the first 24 h was better in the PN Dex group, in which 74.1% of patients reported enjoying a good night’s sleep compared with 33.3% in the IV Dex group and 29.6% in controls (p < 0.0001). Similar values were observed at 48 h: in the PN Dex group, 63% reported a good night’s sleep, vs 29.6% in the IV Dex group and 37% in the control group (p < 0.034). Patient satisfaction was also higher in the PN Dex group: 66.7% were very satisfied compared with 48.1% in the IV Dex group, and 29.6% in the control group (p < 0.025). Time to recovery was similar in all groups (p > 0.2): PN Dex 4.6 days (95% CI: 4.2---5.1), IV Dex 4.3 days (95% CI: 4---4.6), controls 4.7 days (95% CI: 4.1---5.3). In terms of complications, none of the study patients presented paraesthesia, numbness or weakness in the operated limb at the time of discharge, and no cases of injection site haematoma or infection were observed. However, a high rate of postoperative nausea and vomiting was observed in the control group (44.4%) compared with the IV Dex (11.1%) and PN Dex (3.7%) groups (p < 0.0001). Hyperglycaemia was more common in the IV Dex group, although this was not statistically significant. No differences among groups were observed in terms of sensory/motor block of the operated limb at 24 and 48 h post surgery.
Discussion In the management of postoperative pain following knee surgery, our results show that dexamethasone significantly prolongs the duration of the analgesic effect of femoral nerve block with single dose ropivacaine. This finding is consistent with that of other studies evaluating brachial plexus block in upper limb surgery.7---15 However, direct comparisons should be approached with caution due to the extreme heterogeneity of these studies (different sample size, nerve block type and technique used, volume and concentration of LA administered, PN dexamethasone dose used, presence of an additional coadjuvant [clonidine, ephedrine], and inclusion of a control group or an IV dexamethasone group). The prolonged analgesia observed in our sample (on average between 11 and 21 h) are in line with the results reported by Choi et al.7 in their review of 9 studies in upper limb nerve blocks. In this case, the authors found that dexamethasone prolonged the effect of long-acting LA infusion (ropivacaine/bupivacaine) by 576 min. Albrecht et al.,22 in their 2015 analysis of 29 studies in upper limb, sciatic, ankle, peribullar, tranversus abdominis and oral nerve blocks, found that dexamethasone prolonged the effect of long-acting LA by 488 min. The good results obtained in our sample could be due to 2 factors: accurate administration of the blockade, using both ultrasound and neurostimulation to guide placement to achieve a 100% success rate; and the use of ropivacaine, as studies have shown that coadjuvant
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C. Morales-Mu˜ noz et al. Table 2
Summary of findings. IV dexamethasone
PN dexamethasone
Controls
p
Morphine consumption 24 h (mg) Morphine consumption 48 h (mg)
26.3 (18.4---34.2) 43.8 (32.7---54.8)
8.3 (3.9---12.7) 13.3 (7.8---18.6)
26.3 (18.7---33.8) 46.4 (34---58.7)
0.0001 0.0001
Quality of sleep 24 h Good Poor
9 (33.3%) 18 (66.7%)
20 (74.1%) 7 (25.9%)
8 (29.6%) 19 (70.4%)
Quality of sleep 48 h Good Poor
8 (29.6%) 19 (70.4%)
17 (63%) 10 (37%)
10 (37%) 17 (63%)
Patient satisfaction Very satisfied Dissatisfied
13 (48.1%) 14 (51.9%)
18 (66.7%) 9 (33.3%)
8 (29.6%) 19 (70.4%)
Motor block 24 h Normal Limited
23 (85.2%) 4 (14.8%)
21 (77.8%) 6 (22.2%)
25 (92.6%) 2 (7.4%)
Motor block 48 h Normal Limited
26 (96.3%) 1 (3.7%)
25 (92.6%) 2 (7.4%)
25 (92.6%) 2 (7.4%)
Sensory block 24 h Normal Limited
25 (92.6%) 2 (7.4%)
21 (77.8%) 6 (22.2%)
25 (92.6%) 2 (7.4%)
Sensory block 48 h Normal Limited
27 (100%) 0
26 (96.3%) 1 (3.7%)
26 (96.3%) 1 (3.7%)
Complications Nausea/vomiting Hyperglycaemia Nerve damage Infection Others Time to recovery (days)
3 (11.1%) 3 (11.1%) 0 1 (3.7%) 3 (11.1%) 4.3 (4---4.6)
1 (3.7%) 0 0 0 2 (7.4%) 4.6 (4.2---5.1)
12 (44.4%) 1 (3.7%) 0 2 (7.4%) 5 (18.5%) 4.7 (4.1---5.3)
0.001
0.034
0.025
NS
NS
NS
NS
0.0001 NS --NS NS 0.20
CI: confidence interval; h: hours; IV: intravenous; mg: milligrams; NS: no significance; PN: perineural. Data are shown as mean plus 95% confidence interval and number plus percentage.
dexamethasone give better results with this LA than with bupivacaine.8 The significantly lower VAS score observed in the PN Dex group is evidence of the prolonged analgesia provided by femoral block with dexamethasone, which was accompanied by a decreased sensation of pain at 24 and 48 h post surgery. Most studies13,17,21,22 have so far reported lower VAS scores at 24 h, but not at 48 h, at which time point scores are similar among groups. The difference in our findings could be due to the far greater prolongation of femoral block analgesia achieved in our patients compared to earlier studies. It is also interesting to note that better VAS scores at both 24 and 48 h post surgery were obtained in the IV Dex group compared with controls, which we believe could be due to the anti-inflammatory effect of IV dexamethasone. In parallel with the foregoing findings, the PN Dex group showed lower morphine consumption at 24 and 48 h post surgery and a lower rate of postoperative nausea and vomiting, better quality of sleep in the first 24 and 48 h, and greater satisfaction with the technique used. Yet again, these findings
contrast with those reported in the most important studies reviewed,13,21,22 in which longer analgesic effect did not correlate with greater satisfaction or lower morphine consumption. We believe that the prolongation of the analgesic effect obtained with LA and coadjuvant dexamethasone would explain these differences. Although these improved results would be expected to result in a speedier recovery and shorter hospital stay in the PN Dex group, this was in fact not the case. We believe this is due to the fact that postoperative recovery depends on various factors, including the type of surgery and the demographic and clinical characteristics of the patient. Although pain management is important, it is not essential to the recovery process, and considering the demographic and clinical characteristics of our sample (average age of between 68 and 70 years, with a high BMI and considerable comorbidity [ASA II/III]), it is clear that good pain management alone would not be enough to shorten the hospital stay. The exact mechanism of action with which dexamethasone prolongs the analgesic effect of LAs is unknown,
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Analgesic effect of a single-dose of perineural dexamethasone on ultrasound although several hypotheses have been put forward. It has been suggested that the vasoconstrictive action of the drug could delay PN absorption and elimination of LA.18 Some studies, however, claim that dexamethasone attenuates surgery-induced inflammation by suppressing ectopic neural discharge and potentiating the activity of inhibitory potassium channels on nociceptive C-fibres.19 Finally, some authors attribute the analgesic effect of the drug to its systemic anti-inflammatory action. PN administration of dexamethasone is a safe procedure: no cases of dexamethasone-induced neurotoxicity or hyperalgesia were observed in the first 48 h post administration in the 27 cases included in the PN Dex group. Although the use of dexamethasone remains controversial, and concerns have been raised about its off-label use as a coadjuvant in regional nerve block, there is no clear evidence in human trials of neurotoxicity associated with the drug. However, studies in animals suggest a certain level of toxicity when dexamethasone concentration is increased from 66 to 133 g/ml and the drug is used in combination with ropivacaine.23 In our study, dexamethasone was administered at a dose of 400 g/ml, which, in proportion to average weight, is far lower (1.71 g/ml) than the dose determined to be dangerous by Williams et al.23 Recent studies have suggested that nerve damage following spinal administration of steroids is due to particle size, insofar as larger particles can occlude blood vessels and reduce medullary blood flow. Comparing the size of the particles of various steroids, Benzon et al.24 observed that dexamethasone sodium phosphate (used in our study) is a pure liquid steroid with no particles, and could therefore be safer and more effective than other steroids used in connection with nerve block techniques. An analysis of the complication arising from the anaesthetic technique showed no evidence of neurological complications in any study group. According to Brull et al.,25 the risk of nerve damage following peripheral nerve block is estimated to be 0.34%; our sample, therefore, would have been large enough to reveal neurological complications derived from the technique and from the PN administration of dexamethasone. Differences in the incidence of hyperglycaemia at 24 h post surgery were not statistically significant, although a slight trend towards a higher incidence was observed in the IV Dex group. This suggests that administration of PN dexamethasone is safe in diabetic patients, although this hypothesis must be confirmed by specific tolerance studies in this patient population.26 Our study has some limitations. We would point out that as the knee is innervated anteriorly by branches of the femoral nerve, posteriorly by the sciatic nerve, and medially by the obturator nerve, we might have overlooked some major contributors to postoperative pain. Based on the low VAS scores obtained from the PN Dex group and the observations made by Chan et al.,4 we believe the involvement of the sciatic and obturator nerves to be minimal. Nevertheless, further studies combining different nerve blocks with dexamethasone would show whether analgesia is improved by blocking all 3 nerves supplying the knee. We encountered some difficulty in conducting a neurological examination of the operated knee in the immediate postoperative period because the limb was bandaged up to the groin in all patients, and some patients were instructed by the orthopaedic surgeon not to flex the knee for 24 h. This
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made is particularly difficult to accurately evaluate the level of sensory-motor blockade. However, we observed no significant inter-group differences in sensory and motor blockade of the operated limb. Another limitation to our study is the time limit (48 h) for collecting data relating to the primary variables. This prevented us from ascertaining whether VAS scores evened out over time in the 3 groups, or whether some patients presented hyperalgesia or chronic pain. Further studies with longer follow-up and monitoring periods are needed to explore the possibility of these complications presenting in the long-term. The optimal dexamethasone dose for PN administration has yet to be determined. Recent studies27,28 have shown that small doses (4---5 mg) are as effective as high doses (8 mg), leading us to suggest that further studies in low-dose dexamethasone are needed to determine the optimal dose for PN administration. In conclusion, we have shown that PN dexamethasone (8 mg) prolongs the duration of femoral nerve block with 0.5% ropivacaine. It also reduces the sensation of pain and improves quality of sleep in the first 24 and 48 h post surgery, reduces morphine consumption and incidence of adverse effects (nausea and vomiting) in the first 48 h after surgery. This is the first study to compare PN administration of dexamethasone in the context of femoral nerve block in knee replacement surgery in 2 study populations plus a control group. PN dexamethasone has been shown to be safe, with no evidence of neurotoxicity, hyperalgesia or hyperglycaemia in the immediate postoperative period.
Ethical responsibilities Protection of human and animal rights. The authors declare that the procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation and with those of the World Health Organisation and the Helsinki Declaration. Data confidentiality. The authors declare that they have followed the protocols implemented in their place of work regarding the use of patient data in publications. Right to privacy and informed consent. The authors have obtained the informed consent of all patients and/or subjects included in this manuscript. The informed consent forms can be obtained from the author for correspondence.
Conflict of interest The authors have no conflict of interest to declare.
References 1. Horlocker TT. Pain management in total joint arthroplasty: a historical review. Orthopedics. 2010;33:14---9. 2. Wu JWS, Wong YC. Elective unilateral total knee replacement using continuous femoral nerve blockade versus conventional patient-controlled analgesia: perioperative patient management based on a multidisciplinary pathway. Hong Kong Med J. 2014;20:45---51.
+Model
ARTICLE IN PRESS
8 3. Fischer HB, Simanski CJ, Sharp C, Bonnet F, Camu F, Neugebauer EA, et al. A procedure-specific systematic review and consensus recommendations for postoperative analgesia following total knee arthroplasty. Anaesthesia. 2008;63:1105---23. 4. Chan E-Y, Fransen M, Parker DA, Assam PN, Chua N. Femoral nerve blocks for acute postoperative pain after knee replacement surgery. Cochrane Database Syst Rev. 2014;5:CD009941. 5. Pöpping DM, Elia N, Marret E, Wenk M, Tramèr MR. Clonidine as an adjuvant to local anesthetics for peripheral nerve and plexus blocks: a meta-analysis of randomized trials. Anesthesiology. 2009;111:406---15. 6. Abdallah FW, Brull R. Facilitatory effects of perineural dexmedetomidine on neuraxial and peripheral nerve block: a systematic review and meta-analysis. Br J Anaesth. 2013;110:915---25. 7. Choi S, Rodseth R, McCartney CJL. Effects of dexamethasone as a local anaesthetic adjuvant for brachial plexus block: a systematic review and meta-analysis of randomized trials. Br J Anaesth. 2014;112:427---39. 8. Cummings KC, Napierkowski DE, Parra-Sanchez I, Kurz A, Dalton JE, Brems JJSD. Effect of dexamethasone on the duration of interscalene nerve blocks with ropivacaine or bupivacaine. Br J Anaesth. 2011;107:446---53. 9. Movafegh A, Razazian M, Hajimaohamadi F, Meysamie A. Dexamethasone added to lidocaine prolongs axillary brachial plexus blockade. Anesth Analg. 2006;102:263---7. 10. Parrington SJ, O’Donnell D, Chan VWS, Brown-Shreves D, Subramanyam R, Qu M, et al. Dexamethasone added to mepivacaine prolongs the duration of analgesia after supraclavicular brachial plexus blockade. Reg Anesth Pain Med. 2010;35: 422---6. 11. Tandoc MN, Fan L, Kolesnikov S, Kruglov A, Nader ND. Adjuvant dexamethasone with bupivacaine prolongs the duration of interscalene block: a prospective randomized trial. J Anesth. 2011;25:704---9. 12. Vieira P, Pulai I, Tsao GC, Manikantan P, Keller B, Connelly NR. Dexamethasone with bupivacaine increases duration of analgesia in ultrasound-guided interscalene brachial plexus blockade. Eur J Anaesthesiol. 2010;27:285---8. 13. Desmet M, Braems H, Reynvoet M, Plasschaert S, Van Cauwelaert J, Pottel H, et al. I.V. and perineural dexamethasone are equivalent in increasing the analgesic duration of a singleshot interscalene block with ropivacaine for shoulder surgery: a prospective, randomized, placebo-controlled study. Br J Anaesth. 2013;111:445---52. 14. Golwala MP, Swadia VN, Dhimar AA. Pain relief by dexamethasone as an adjuvant to local anaesthetics in supraclavicular brachial plexus block. J Anaesthesiol Clin Pharmacol. 2009;25:285---8. 15. Kim YJ, Lee GY, Kim DY, Kim CH, Baik H-J, Heo S. Dexamathasone added to levobupivacaine improves postoperative
C. Morales-Mu˜ noz et al.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
analgesia in ultrasound guided interscalene brachial plexus blockade for arthroscopic shoulder surgery. Korean J Anesthesiol. 2012;62:130---4. Rahangdale R, Kendall MC, McCarthy RJ, Tureanu L, Doty R Jr, Weingart A, et al. The effects of perineural versus intravenous dexamethasone on sciatic nerve blockade outcomes: a randomized, double-blind, placebo-controlled study. Anesth Analg. 2014;118:1113---9. Fredrickson Fanzca MJ, Danesh-Clough TK, White R. Adjuvant dexamethasone for bupivacaine sciatic and ankle blocks: results from 2 randomized placebo-controlled trials. Reg Anesth Pain Med. 2013;38:300---7. Attardi B, Takimoto K, Gealy R, Severns C, Levitan ES. Glucocorticoid induced up-regulation of a pituitary K+ channel mRNA in vitro and in vivo. Recept Channels. 1993;1:287---93. Johansson A, Hao J, Sjölund B. Local corticosteroid application blocks transmission in normal nociceptive C-fibres. Acta Anaesthesiol Scand. 1990;34:335---8. Ma R, Wang X, Lu C, Li C, Cheng Y, Ding G, et al. Dexamethasone attenuated bupivacaine-induced neuron injury in vitro through a threonine-serine protein kinase B-dependent mechanism. Neuroscience. 2010;167:329---42. Marks R, Barlow JW, Funder JW. Steroid-induced vasoconstriction: glucocorticoid antagonist studies. J Clin Endocrinol Metab. 1982;54:1075---7. Albrecht E, Kern C, Kirkham KR. A systematic review and metaanalysis of perineural dexamethasone for peripheral nerve blocks. Anaesthesia. 2015;70:71---83. Williams BA, Hough KA, Tsui BYK, Ibinson JW, Gold MS, Gebhart GF. Neurotoxicity of adjuvants used in perineural anesthesia and analgesia in comparison with ropivacaine. Reg Anesth Pain Med. 2011;36:225---30. Benzon HT, Chew T-L, McCarthy RJ, Benzon HA, Walega DR. Comparison of the particle sizes of different steroids and the effect of dilution: a review of the relative neurotoxicities of the steroids. Anesthesiology. 2007;106:331---8. Brull R, McCartney CJL, Chan VWS, el-Beheiry H. Neurological complications after regional anesthesia: contemporary estimates of risk. Anesth Analg. 2007;104:965---74. Williams Ba, Murinson BB, Grable BR, Orebaugh SL. Future considerations for pharmacologic adjuvants in single-injection peripheral nerve blocks for patients with diabetes mellitus. Reg Anesth Pain Med. 2009;34:445---57. Persec J, Persec Z, Kopljar M, Zupcic M, Sakic L, Zrinjscak IK, et al. Low-dose dexamethasone with levobupivacaine improves analgesia after supraclavicular brachial plexus blockade. Int Orthop. 2014;38:101---5. Knezevic NN, Anantamongkol U, Candido KD. Perineural dexamethasone added to local anesthesia for brachial plexus block improves pain but delays block onset and motor blockade recovery. Pain Phys. 2015;18:1---14.