Eur J Anaesthesiol 2015; 32:650–655
ORIGINAL ARTICLE
Dose-dependency of dexamethasone on the analgesic effect of interscalene block for arthroscopic shoulder surgery using ropivacaine 0.5% A randomised controlled trial Jae Hee Woo, Youn Jin Kim, Dong Yeon Kim and Sooyoung Cho BACKGROUND Dexamethasone prolongs the duration of single-shot interscalene brachial plexus block (SISB). However, dose-dependency of dexamethasone as an adjuvant for SISB remains insufficiently understood. OBJECTIVE The objective of this study is to evaluate the effect of different doses of dexamethasone on the duration of SISB using ropivacaine 0.5%. DESIGN A randomised, double-blind controlled trial. SETTING Single university tertiary care centre. PATIENTS One hundred and forty-four patients scheduled for elective arthroscopic shoulder surgery were allocated randomly to one of four groups. INTERVENTIONS Patients received 12 ml of ropivacaine 0.5% in 0.9% saline (control group), or containing dexamethasone 2.5, 5.0 or 7.5 mg for SISB. MAIN OUTCOME MEASURES The primary endpoint was the time to the first analgesic request. Pain scores and adverse effects were also assessed up to 48 h postoperatively.
RESULTS Inclusion of dexamethasone 2.5, 5.0 and 7.5 mg resulted in significant (P < 0.001) increases in time to the first analgesic request by factors of 1.6, 2.2 and 1.8, respectively. The percentages of patients not requiring analgesics in the first 48 h postoperatively with dexamethasone 0.0, 2.5, 5.0 and 7.5 mg were 3, 22, 39 and 33%, respectively (P < 0.001). There were no significant effects on pain scores or incidences of adverse effects. CONCLUSION Dexamethasone demonstrated significant beneficial dose-dependent effects on duration to the first analgesic request, the number of patients not requiring analgesics and analgesic use in the first 48 h after SISB for arthroscopic shoulder surgery. There were no significant effects on pain scores or incidences of adverse effects. TRIAL REGISTRATION the trial was registered with the Clinical Trial Registry of Korea: https://cris.nih.go.kr/cris/ index.jsp. Identifier: KCT0001078 Published online 17 January 2015
Introduction Arthroscopic shoulder surgery (ASS) is associated with considerable postoperative pain.1,2 Several modalities have been investigated for postoperative analgesia, including single-shot interscalene brachial plexus block (SISB), continuous interscalene brachial plexus block (CISB), subacromial injection of local anaesthetic and suprascapular nerve block.2,3 CISB can provide better analgesia than other methods, but has not gained popularity because it is
technically challenging and requires more time and effort from anaesthesiologists for patient care.2 Despite its limited duration of analgesia, SISB is widely used because of its excellent analgesic effect and the relative ease of the procedure.2 An effective adjuvant that prolongs the duration of SISB analgesia may be useful when CISB is not practical. Previous studies investigating various adjuvants including clonidine,4 ketamine5 and epinephrine6 in
From the Department of Anaesthesiology and Pain Medicine, School of Medicine, Ewha Womans University, Seoul, Korea Correspondence to Youn Jin Kim, MD, PhD, Department of Anaesthesiology and Pain Medicine, School of Medicine, Ewha Womans University, 911-1, Mok-dong, Yangcheon-gu, Seoul 158-710, Korea Tel: +82 2 2650 2885; fax: +82 2 2655 2924; e-mail: [email protected] 0265-0215 Copyright ß 2015 European Society of Anaesthesiology. All rights reserved.
DOI:10.1097/EJA.0000000000000213
Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
Dexamethasone dose and interscalene blocks 651
prolonging the duration of SISB have proved unsatisfactory. However, dexamethasone has been found to extend the duration of SISB-induced analgesia significantly.7–10 The doses of dexamethasone have varied in different studies such that the dose-dependency relationship on the duration of sensory block with ropivacaine SISB remains unknown. Until now, most studies concerning SISB have used relatively large volumes of local anaesthetic, although they combined general anaesthesia and SISB for ASS.7–11 In the present study, we used 12 ml of ropivacaine 0.5% based on our experience of more than 5 years and on previous results.12,13 In this double-blind, randomised and prospective trial, we investigated the effects of different doses of dexamethasone as a perineural adjuvant on the duration of analgesia induced by ropivacaine SISB.
Patients and methods Ethical approval for the study (ECT 13-43A-29) was provided by the local ethics committee of Ewha Womans University, Seoul, Korea (Chairperson, Professor W.B. Pyun) on 18 December 2013. The trial was registered with the Clinical Trial Registry of Korea with an assigned number of KCT0001078, and written informed consent was obtained from all patients. Patients aged 20 to 70 years with American Society of Anaesthesiologists’ (ASA) physical status 1 or 2, scheduled for elective ASS, were enrolled. Exclusion criteria were patient refusal, presence of coagulopathy, infection at the site of the block, any neurological deficit in the surgical limb, severe lung disease, contralateral diaphragmatic paralysis, systemic glucocorticoid use, chronic opioid use, peptic ulcer disease, uncontrolled diabetes mellitus and a known allergy to ropivacaine. A total volume of 12 ml study drug was made with the final concentration being ropivacaine 0.5%. Patients were allocated randomly to one of four groups to receive an injection of 12 ml of a solution containing 8ml of ropivacaine 0.75% (60 mg) and 4 ml of 0.9% saline or dexamethasone for SISB using a computer-generated randomisation table: (1) (2) (3) (4)
ropivacaine ropivacaine ropivacaine ropivacaine
5 mg ml1 5 mg ml1 5 mg ml1 5 mg ml1
with with with with
0.9% saline (control); dexamethasone 2.5 mg; dexamethasone 5.0 mg; dexamethasone 7.5 mg.
An anaesthesiologist blinded to the dose assignments prepared all of the study drugs. The patients and attending anaesthesiologists participating in the study were unaware of the dose assignments. On arrival at the operating room, standard ASA monitors were used throughout the surgery. All patients received a standardised SISB under ultrasound guidance (SonoSite; M-Turbo; SonoSite; Bothell, Washington, USA). The
blocks were performed by one experienced anaesthesiologist and were facilitated by sedation using intravenous midazolam (1 to 3 mg) and fentanyl (25 to 50 mg). The patient was placed in a supine position with the head turned away from the side to be blocked. Using a linear probe (5 to 12 MHz), hypoechoic nerve roots or the superior trunk located between the anterior and middle scalene muscles were identified in the short-axis view. After sterile skin preparation, the point where the C5, C6 and C7 roots or superior trunk were most visible was selected. A 50-mm, 22 gauge insulated needle (Stimuplex A; B-Braun, Melsungen, Germany) was used, and the tip was advanced towards the C5 and C6 roots or superior trunk within the sheath using the in-plane method. After localisation and negative aspiration, all patients received SISB with 12 ml of the study solution according to the group allocation. After intravenous injection of glycopyrronium 0.2 mg, general anaesthesia was induced using thiopentone 4 mg kg1 and fentanyl 1 to 2 mg kg1. Tracheal intubation was facilitated using rocuronium 0.6 mg kg1. Anaesthesia was maintained using a 50% oxygen in air mixture and sevoflurane (1.0 to 1.5 minimum alveolar concentrations) to maintain the bispectral index value between 40 and 60 and SBP within 20% of the baseline value. Patients were placed in the lateral decubitus position, and all of the operations were performed by one surgeon. Patients were extubated in the operating room after reversal of residual muscle relaxation. In the recovery room, patients were assessed by an anaesthesiologist for pain score, weakness, numbness and complications or side effects such as nausea, vomiting, dizziness, respiratory difficulties and Horner syndrome. The patients underwent chest radiography to rule out phrenic nerve palsy. A doctor blinded to the groups visited the patients and evaluated pain using a numerical rating scale (NRS; 0, no pain; 10, most severe pain imaginable) up to 48 h from the time of arrival in the recovery room. The patients were given i.v. tramadol 100 mg, up to three times a day when NRS was at least 3 or analgesia was requested. In the case of insufficient analgesia, patients were treated with i.v. ketorolac 30 mg up to 90 mg a day. Individual doses given were recorded.
Statistical analysis The Statistical Package for the Social Sciences (SPSS; 18.0, Chicago, Illinois, USA) was used for statistical analysis. The primary endpoint was the time to the first analgesic request, defined as the interval between SISB and the first administration of analgesic. Secondary outcomes included the number of patients not requiring analgesics, analgesic use, pain scores and incidences of arm weakness, arm numbness and adverse effects for 48 h postoperatively. From our prior experience and that of Cummings et al.,8 we expected a block duration of 10 h with ropivacaine alone, and an 11-h difference between
Eur J Anaesthesiol 2015; 32:650–655 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
652 Woo et al.
the control and treatment groups was considered clinically significant. Therefore, a sample size of 32 patients (a ¼ 0.05, power ¼ 80%) per group was calculated (logrank test). Correction for dropouts suggested n ¼ 36 patients per group. Continuous variables were analysed by analysis of variance or the Kruskal–Wallis test after assessment for normality and are presented as mean SD or as median and interquartile range (IQR) as appropriate. Categorical variables were analysed using the x2 or Fisher exact tests. The time to the first analgesic request was analysed by Kaplan–Meier survival analysis with the logrank test and the Cox proportional hazards model to estimate likelihood ratios adjusted for covariates. The Bonferroni correction was applied for three comparisons against the control group and the corrected P values are presented. The secondary outcomes (number of patients who did not require analgesics, and the incidences of arm weakness, numbness and adverse effects) were analysed using linear-by-linear association x2 test. Tramadol and ketorolac use and pain scores were analysed using the linear regression test after conversion to the van der Waerden normal scores because those data were not normally distributed. A P value less than 0.05 was considered statistically significant.
Results One hundred and fifty-nine patients were assessed for eligibility and 15 were ineligible because of the exclusion criteria or patient refusal; in total, 144 patients were included in the analysis. Figure 1 illustrates the allocation process according to the Consolidated Standards of
Reporting Trials (CONSORT) statement. Baseline covariates were well balanced across the randomised groups (Table 1). Perioperative clinical details such as the preoperative pain score, duration of operation and anaesthesia and type of surgery were distributed evenly among the four groups (Table 2). Dexamethasone significantly (log-rank test P < 0.001) prolonged the duration of analgesia. Kaplan–Meier curves were used to measure the time to the first analgesic request during the first postoperative 48 h. In the control group, the time to first analgesic request was a median (IQR) of 11.0 (8.2 to 14.4) h. Compared with the control group, dexamethasone doses of 2.5, 5 and 7.5 mg resulted in times to first analgesic request of 17.3 (12.2 to 22.0) h (P ¼ 0.005), 24.2 (15.8 to 49.8) h (P < 0.001) and 19.9 (15.5 to 49.6) h (P < 0.001), respectively. A Cox proportional hazards model for the time to the first analgesic request was performed including the following variables: dexamethasone dose, sex, age and type of surgery. None of the variables except dose of dexamethasone was significant (Fig. 2). Table 3 summarises the pain scores and analgesic requirements during the first postoperative 48 h. There was a dose-dependent increase in the number of patients not requiring analgesics for the first postoperative 48 h with dexamethasone (P < 0.001). Likewise, there were dose-dependent reductions in the uses of tramadol (P ¼ 0.003) and ketorolac (P < 0.0001) with dexamethasone. There were no dose-dependent effects on NRS at each time point. The other secondary outcomes are
Fig. 1
Enrolment
Assessed for eligibility (n = 159)
Excluded (n = 159) ♦ Notmeeting inclusion criteria (n = 8) ♦ Declined to participate (n = 7)
Randomised (n = 144)
Allocation Allocated to no addition of dexamethasone (n = 36)
Allocated to addition of dexamethasone 2.5 mg (n = 36)
Allocated to addition of dexamethasone 5 mg (n = 36)
Allocated to addition of dexamethasone 7.5 mg (n = 36)
Follow-up No patients lost to follow-up for the study through postoperative 48h
Analysis Analysed (n = 36)
Analysed (n = 36)
Analysed (n = 36)
Analysed (n = 36)
CONSORT flow chart.
Eur J Anaesthesiol 2015; 32:650–655 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
Dexamethasone dose and interscalene blocks 653
Table 1
Patient characteristics
Age (years) Weight (kg) Sex (male:female) ASA physical status (1 : 2)
Saline 0.9% (n U 36)
Dex 2.5 mg (n U 36)
Dex 5 mg (n U 36)
Dex 7.5 mg (n U 36)
54.4 17.8 66.5 12.1 23 : 13 9 : 27
50.8 16.1 67.8 14.3 22 : 14 18 : 18
54.3 15.0 66.1 10.1 25 : 11 12 : 24
47.3 17.5 74.7 24.4 30 : 6 17 : 19
Values are mean SD or count. The groups were similar in respect of baseline variables. ASA, American Society of Anesthesiologists; Dex, dexamethasone.
summarised in Table 4. There were no significant differences in the incidences of arm weakness, numbness or adverse effects including nausea, vomiting, dizziness, phrenic nerve palsy, Horner syndrome and hoarseness during the study period. During the second postoperative 24 h, arm weakness was observed in one patient who had received dexamethasone 2.5 mg and arm numbness was noted in three patients who had received 5 mg. However, all neurological signs had resolved by the following day. At day 14 of follow-up, no patient reported persistent symptoms such as weakness, paraesthesiae or numbness of the arm.
Discussion Our results have shown that perineural dexamethasone significantly prolongs the analgesia induced by ropivacaine SISB and that this effect is dose-dependent. Although the most noticeable prolongation of analgesia was observed with dexamethasone 5 mg, there was a significant dose-dependent increase in the number of patients not requiring analgesics with dexamethasone. There was also a beneficial dose-dependent effect on analgesic use. This randomised study was designed to minimise possible biases by using a single anaesthesiologist and surgeon. The types of surgery were also distributed evenly among the groups. Furthermore, a Cox proportional hazards model revealed that the type of surgery did not affect our results. Previous authors have performed SISB using 20 to 40 ml of 0.5 to 0.75% ropivacaine or bupivacaine for SISB,7–11 but we used 12 ml of ropivacaine 0.5% (60 mg) for SISB. In the study by Desmet et al.,7 SISB was performed with 30 ml of ropivacaine 0.5% followed by general anaesthesia for ASS. They reported a high incidence of Horner syndrome and hoarseness, although the duration of analgesia and the amount of analgesics used were comparable with our results using a lower volume of Table 2
ropivacaine 0.5%. No patient experienced Horner syndrome or hoarseness in our study. We evaluated doses of perineural dexamethasone up to 7.5 mg. In a previous study using SISB as surgical anaesthesia for ASS, Tandoc et al.9 used 40 ml of bupivacaine 0.5%. They found that doses of 4 and 8 mg of perineural dexamethasone prolonged sensory blocks to 21.6 2.4 h and 25.2 1.9 h, respectively, although these were not significantly different. This result is comparable with our study, which showed an analgesic duration of 24.2 (15.8 to 49.8) h with dexamethasone 5 mg and no further additional benefit with 7.5 mg. The mechanisms behind the beneficial effect of dexamethasone and the route of administration remain to be determined. It has been suggested that the effect is mediated by direct blockade of transmission in nociceptive C-fibres, reducing the release of inflammatory mediators and ectopic neuronal discharge, and upregulation of potassium channels.14–16 Recently, the route of dexamethasone administration has been debated and several studies have reported that intravenous dexamethasone can produce opioid-sparing effects under various situations,17 and that there was no difference in the analgesic effect between perineural and systemic administration.7,18,19 This reduces the probability that dexamethasone exerts its action by a direct perineural effect. However, some evidence has suggested that dexamethasone exerts its activity via a perineural effect. Whereas a meta-analysis of 24 randomised trials suggested that a single dose of intravenous dexamethasone at doses less than 0.1 mg kg1 did not produce an opioid-sparing effect,17 even 2.5 mg of perineural dexamethasone prolonged the length of the sensory block in our study. Kawanishi et al.11 demonstrated that 4 mg of perineural dexamethasone as an adjuvant for SISB using 20 ml ropivacaine 0.75% produced a significant advantage over intravenous dexamethasone administration.
Perioperative data
Preoperative pain (NRS) Operation time (min) Anaesthetic time (min) Surgery, n (%) Rotator cuff repair Labral repair Arthroscopic capsular release Greater tuberosity reconstruction
Saline 0.9% (n U 36)
Dex 2.5 mg (n U 36)
Dex 5 mg (n U 36)
Dex 7.5 mg (n U 36)
2.1 1.4 81.3 30.7 131.4 35.7
2.3 1.5 79.2 30.8 131.5 34.4
2.1 1.5 87.9 49.4 138.6 52.1
2.8 1.7 79.3 35.34 130.8 39.6
29 7 0 0
(80.6) (19.4) (0) (0)
26 9 1 0
(72.2) (25.0) (2.8) (0)
24 8 1 3
(66.7) (22.2) (2.8) (8.3)
26 10 0 0
(80.6) (27.8) (0) (0)
Values are mean SD or count (%). Data were similar among groups. Dex, dexamethasone; NRS, numerical rating scale.
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654 Woo et al.
Fig. 2
Proportion of patients not requesting analgesia
1.0
0.9% saline Dex 2.5 mg Dex 5 mg Dex 7.5 mg
0.8
0.6
* *
0.4
* 0.2
0.0 0
500
1000
1500
2000
2500
3000
Time to first analgesic request (min) Kaplan–Meier survival plot. Dex, dexamethasone. Corrected P < 0.05 compared with control group (0.9% saline).
There have been concerns about the use of perineural dexamethasone. Because trials require large sample sizes to come to reliable conclusions about safety in respect of extremely rare events, there is no alternative but to rely on the results of experimental studies. Several animal experiments have demonstrated no significant long-term adverse effects.20,21 Moreover, epidural injections of corticosteroids have long been used to treat radiculopathy and, to date, no clinical trial has reported any neurological complications attributed to dexamethasone.16 Neural injury can also be related to needle-induced direct trauma. In our study, we performed SISB under ultrasound guidance using the in-plane approach to minimise the risk of trauma to nerves. The appropriate spread of local anaesthetic within the sheath of the interscalene brachial plexus was ascertained during administration. Thus, local anaesthetics were allowed to spread with sufficient perfusion throughout the brachial plexus and SISB was achieved successfully in all patients without persistent neurological complications.
Table 3
There are several limitations of the present study. First, our sample sizes are to too small to discuss clinical or statistically significant differences between different dexamethasone doses. This study was also not designed to find the optimal dose of dexamethasone. Our results only confirm a significant beneficial dose-dependency with dexamethasone. Second, we focused on outcomes during the acute postoperative period and did not specifically evaluate long-term complication profiles. However, on the day of discharge and on day 14 of follow-up, no patient reported neurological complications. Third, we did not analyse changes in the postoperative blood glucose concentration. One study showed that the elevation of blood glucose after SISB using dexamethasone 10 mg was statistically significant but clinically irrelevant. Fourth, given the extremely low rate of persistent neurological complications and safety concerns with perineural dexamethasone use, further studies are warranted to clarify dexamethasone administration as an adjuvant.
Pain intensity and analgesic requirements for the first postoperative 48 h Saline 0.9% (n U 36)
Patients not requiring analgesicsM Tramadol use (n)MM Ketorolac use (n)MM NRS at 6 h NRS at 12 h NRS at 24 h NRS at 48 h
1 2 2 1 3 2 1
(2.8%) (1 to 3) (1 to 3) (0 to 3) (1 to 4) (1 to 3) (0 to 2)
Dex 2.5 mg (n U 36) 8 1 1 0 1 1 0
(22.2%) (0 to 1) (0 to 1) (0 to 1) (0 to 2) (0 to 3) (0 to 1)
Dex 5 mg (n U 36) 14 1 1 0 1 2.5 0
(38.9%) (0 to 1) (0 to 1) (0 to 1) (0 to 3) (0.25 to 5) (0 to 2)
Dex 7.5 mg (n U 36) 12 1 1 0 1 1.5 0
(33.3%) (0 to 1) (0 to 1) (0 to 2) (0 to 2) (1 to 4) (0 to 1)
Values are median (IQR) or count (percentage). There were no significant differences among groups. Data were similar among groups. Dex, dexamethasone; NRS, numerical rating scale. M P < 0.001 by linear-by-linear association x2 test. MM P < 0.05 by linear regression analysis using the van der Waerden normal scores.
Eur J Anaesthesiol 2015; 32:650–655 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
Dexamethasone dose and interscalene blocks 655
Table 4
Secondary outcome variables Saline 0.9% (n U 36)
Dex 2.5 mg (n U 36)
Dex 5 mg (n U 36)
Dex 7.5 mg (n U 36)
8 0
12 1
14 0
15 0
18 0 6 0 2 1 0 0 0
15 0 3 0 1 2 0 0 0
18 3 8 0 2 1 0 0 0
22 0 8 1 2 4 0 0 0
Arm weakness 0 to 24 h 24 to 48 h Arm numbness 0 to 24 h 24 to 48 h Nausea Vomiting Dizziness Phrenic nerve palsy Horner syndrome Hoarseness Dyspnoea
Values are counts. Dex, dexamethasone. There were no significant differences by x2 or Fisher exact tests and no significant dose-dependent trend.
In conclusion, we have shown that perineural dexamethasone has significant beneficial dose-dependent effects on the time to the first analgesic request, the number of patients not requiring analgesics and analgesic use during the first postoperative 48 h when added to 12 ml ropivacaine 0.5% for SISB in ASS.
Acknowledgements relating to this article
8
9
10
11
Assistance with the study: none. Financial support and sponsorship: none.
12
Conflict of interest: none. Presentation: preliminary data from this study were presented at the annual meeting of the European Society of Anaesthesiology, May 2014, Stockholm.
References 1 2
3
4
5
6
7
Wilson AT, Nicholson E, Burton L, Wild C. Analgesia for day-case shoulder surgery. Br J Anaesth 2004; 92:414–415. Fredrickson MJ, Krishnan S, Chen CY. Postoperative analgesia for shoulder surgery: a critical appraisal and review of current techniques. Anaesthesia 2010; 65:608–624. Fontana C, Di Donato A, Di Giacomo G, et al. Postoperative analgesia for arthroscopic shoulder surgery: a prospective randomized controlled study of intraarticular, subacromial injection, interscalenic brachial plexus block and intraarticular plus subacromial injection efficacy. Eur J Anaesthesiol 2009; 26:689–693. Culebras X, Van Gessel E, Hoffmeyer P, Gamulin Z. Clonidine combined with a long acting local anesthetic does not prolong postoperative analgesia after brachial plexus block but does induce hemodynamic changes. Anesth Analg 2001; 92:199–204. Lee IO, Kim WK, Kong MH, et al. No enhancement of sensory and motor blockade by ketamine added to ropivacaine interscalene brachial plexus blockade. Acta Anaesthesiol Scand 2002; 46:821–826. Sinnott CJ, Cogswell IL, Johnson A, Strichartz GR. On the mechanism by which epinephrine potentiates lidocaine’s peripheral nerve block. Anesthesiology 2003; 98:181–188. Desmet M, Braems H, Reynvoet M, et al. I.V. and perineural dexamethasone are equivalent in increasing the analgesic duration of a single-shot interscalene block with ropivacaine for shoulder surgery: a prospective, randomized, placebo-controlled study. Br J Anaesth 2013; 111:445–452.
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Cummings KC 3rd, Napierkowski DE, Parra-Sanchez I, et al. Effect of dexamethasone on the duration of interscalene nerve blocks with ropivacaine or bupivacaine. Br J Anaesth 2011; 107:446–453. Tandoc MN, Fan L, Kolesnikov S, et al. Adjuvant dexamethasone with bupivacaine prolongs the duration of interscalene block: a prospective randomized trial. J Anesth 2011; 25:704–709. Vieira PA, Pulai I, Tsao GC, et al. Dexamethasone with bupivacaine increases duration of analgesia in ultrasound-guided interscalene brachial plexus blockade. Eur J Anaesthesiol 2010; 27:285–288. Kawanishi R, Yamamoto K, Tobetto Y, et al. Perineural but not systemic lowdose dexamethasone prolongs the duration of interscalene block with ropivacaine: a prospective randomized trial. Local Reg Anesth 2014; 7:5–9. Gautier P, Vandepitte C, Ramquet C, et al. The minimum effective anesthetic volume of 0.75% ropivacaine in ultrasound-guided interscalene brachial plexus block. Anesth Analg 2011; 113:951–955. Krone SC, Chan VW, Regan J, et al. Analgesic effects of low-dose ropivacaine for interscalene brachial plexus block for outpatient shoulder surgery – a dose-finding study. Reg Anesth Pain Med 2001; 26:439–443. Attardi B, Takimoto K, Gealy R, et al. Glucocorticoid induced up-regulation of a pituitary Kþ channel mRNA in vitro and in vivo. Receptors Channels 1993; 1:287–293. Johansson A, Hao J, Sjolund B. Local corticosteroid application blocks transmission in normal nociceptive C-fibres. Acta Anaesthesiol Scand 1990; 34:335–338. Choi S, Rodseth R, McCartney CJ. 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; 112:427–439. De Oliveira GS Jr, Almeida MD, Benzon HT, McCarthy RJ. Perioperative single dose systemic dexamethasone for postoperative pain: a metaanalysis of randomized controlled trials. Anesthesiology 2011; 115: 575–588. 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; 38:300–307. Rahangdale R, Kendall MC, McCarthy RJ, et al. The effects of perineural versus intravenous dexamethasone on sciatic nerve blockade outcomes: a randomized, double-blind, placebo-controlled study. Anesth Analg 2014; 118:1113–1119. Ma R, Wang X, Lu C, et al. Dexamethasone attenuated bupivacaineinduced neuron injury in vitro through a threonine-serine protein kinase Bdependent mechanism. Neuroscience 2010; 167:329–342. Williams BA, Hough KA, Tsui BY, et al. Neurotoxicity of adjuvants used in perineural anesthesia and analgesia in comparison with ropivacaine. Reg Anesth Pain Med 2011; 36:225–230.
Eur J Anaesthesiol 2015; 32:650–655 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
ORIGINAL ARTICLE
Dose-dependency of dexamethasone on the analgesic effect of interscalene block for arthroscopic shoulder surgery using ropivacaine 0.5% A randomised controlled trial Jae Hee Woo, Youn Jin Kim, Dong Yeon Kim and Sooyoung Cho BACKGROUND Dexamethasone prolongs the duration of single-shot interscalene brachial plexus block (SISB). However, dose-dependency of dexamethasone as an adjuvant for SISB remains insufficiently understood. OBJECTIVE The objective of this study is to evaluate the effect of different doses of dexamethasone on the duration of SISB using ropivacaine 0.5%. DESIGN A randomised, double-blind controlled trial. SETTING Single university tertiary care centre. PATIENTS One hundred and forty-four patients scheduled for elective arthroscopic shoulder surgery were allocated randomly to one of four groups. INTERVENTIONS Patients received 12 ml of ropivacaine 0.5% in 0.9% saline (control group), or containing dexamethasone 2.5, 5.0 or 7.5 mg for SISB. MAIN OUTCOME MEASURES The primary endpoint was the time to the first analgesic request. Pain scores and adverse effects were also assessed up to 48 h postoperatively.
RESULTS Inclusion of dexamethasone 2.5, 5.0 and 7.5 mg resulted in significant (P < 0.001) increases in time to the first analgesic request by factors of 1.6, 2.2 and 1.8, respectively. The percentages of patients not requiring analgesics in the first 48 h postoperatively with dexamethasone 0.0, 2.5, 5.0 and 7.5 mg were 3, 22, 39 and 33%, respectively (P < 0.001). There were no significant effects on pain scores or incidences of adverse effects. CONCLUSION Dexamethasone demonstrated significant beneficial dose-dependent effects on duration to the first analgesic request, the number of patients not requiring analgesics and analgesic use in the first 48 h after SISB for arthroscopic shoulder surgery. There were no significant effects on pain scores or incidences of adverse effects. TRIAL REGISTRATION the trial was registered with the Clinical Trial Registry of Korea: https://cris.nih.go.kr/cris/ index.jsp. Identifier: KCT0001078 Published online 17 January 2015
Introduction Arthroscopic shoulder surgery (ASS) is associated with considerable postoperative pain.1,2 Several modalities have been investigated for postoperative analgesia, including single-shot interscalene brachial plexus block (SISB), continuous interscalene brachial plexus block (CISB), subacromial injection of local anaesthetic and suprascapular nerve block.2,3 CISB can provide better analgesia than other methods, but has not gained popularity because it is
technically challenging and requires more time and effort from anaesthesiologists for patient care.2 Despite its limited duration of analgesia, SISB is widely used because of its excellent analgesic effect and the relative ease of the procedure.2 An effective adjuvant that prolongs the duration of SISB analgesia may be useful when CISB is not practical. Previous studies investigating various adjuvants including clonidine,4 ketamine5 and epinephrine6 in
From the Department of Anaesthesiology and Pain Medicine, School of Medicine, Ewha Womans University, Seoul, Korea Correspondence to Youn Jin Kim, MD, PhD, Department of Anaesthesiology and Pain Medicine, School of Medicine, Ewha Womans University, 911-1, Mok-dong, Yangcheon-gu, Seoul 158-710, Korea Tel: +82 2 2650 2885; fax: +82 2 2655 2924; e-mail: [email protected] 0265-0215 Copyright ß 2015 European Society of Anaesthesiology. All rights reserved.
DOI:10.1097/EJA.0000000000000213
Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
Dexamethasone dose and interscalene blocks 651
prolonging the duration of SISB have proved unsatisfactory. However, dexamethasone has been found to extend the duration of SISB-induced analgesia significantly.7–10 The doses of dexamethasone have varied in different studies such that the dose-dependency relationship on the duration of sensory block with ropivacaine SISB remains unknown. Until now, most studies concerning SISB have used relatively large volumes of local anaesthetic, although they combined general anaesthesia and SISB for ASS.7–11 In the present study, we used 12 ml of ropivacaine 0.5% based on our experience of more than 5 years and on previous results.12,13 In this double-blind, randomised and prospective trial, we investigated the effects of different doses of dexamethasone as a perineural adjuvant on the duration of analgesia induced by ropivacaine SISB.
Patients and methods Ethical approval for the study (ECT 13-43A-29) was provided by the local ethics committee of Ewha Womans University, Seoul, Korea (Chairperson, Professor W.B. Pyun) on 18 December 2013. The trial was registered with the Clinical Trial Registry of Korea with an assigned number of KCT0001078, and written informed consent was obtained from all patients. Patients aged 20 to 70 years with American Society of Anaesthesiologists’ (ASA) physical status 1 or 2, scheduled for elective ASS, were enrolled. Exclusion criteria were patient refusal, presence of coagulopathy, infection at the site of the block, any neurological deficit in the surgical limb, severe lung disease, contralateral diaphragmatic paralysis, systemic glucocorticoid use, chronic opioid use, peptic ulcer disease, uncontrolled diabetes mellitus and a known allergy to ropivacaine. A total volume of 12 ml study drug was made with the final concentration being ropivacaine 0.5%. Patients were allocated randomly to one of four groups to receive an injection of 12 ml of a solution containing 8ml of ropivacaine 0.75% (60 mg) and 4 ml of 0.9% saline or dexamethasone for SISB using a computer-generated randomisation table: (1) (2) (3) (4)
ropivacaine ropivacaine ropivacaine ropivacaine
5 mg ml1 5 mg ml1 5 mg ml1 5 mg ml1
with with with with
0.9% saline (control); dexamethasone 2.5 mg; dexamethasone 5.0 mg; dexamethasone 7.5 mg.
An anaesthesiologist blinded to the dose assignments prepared all of the study drugs. The patients and attending anaesthesiologists participating in the study were unaware of the dose assignments. On arrival at the operating room, standard ASA monitors were used throughout the surgery. All patients received a standardised SISB under ultrasound guidance (SonoSite; M-Turbo; SonoSite; Bothell, Washington, USA). The
blocks were performed by one experienced anaesthesiologist and were facilitated by sedation using intravenous midazolam (1 to 3 mg) and fentanyl (25 to 50 mg). The patient was placed in a supine position with the head turned away from the side to be blocked. Using a linear probe (5 to 12 MHz), hypoechoic nerve roots or the superior trunk located between the anterior and middle scalene muscles were identified in the short-axis view. After sterile skin preparation, the point where the C5, C6 and C7 roots or superior trunk were most visible was selected. A 50-mm, 22 gauge insulated needle (Stimuplex A; B-Braun, Melsungen, Germany) was used, and the tip was advanced towards the C5 and C6 roots or superior trunk within the sheath using the in-plane method. After localisation and negative aspiration, all patients received SISB with 12 ml of the study solution according to the group allocation. After intravenous injection of glycopyrronium 0.2 mg, general anaesthesia was induced using thiopentone 4 mg kg1 and fentanyl 1 to 2 mg kg1. Tracheal intubation was facilitated using rocuronium 0.6 mg kg1. Anaesthesia was maintained using a 50% oxygen in air mixture and sevoflurane (1.0 to 1.5 minimum alveolar concentrations) to maintain the bispectral index value between 40 and 60 and SBP within 20% of the baseline value. Patients were placed in the lateral decubitus position, and all of the operations were performed by one surgeon. Patients were extubated in the operating room after reversal of residual muscle relaxation. In the recovery room, patients were assessed by an anaesthesiologist for pain score, weakness, numbness and complications or side effects such as nausea, vomiting, dizziness, respiratory difficulties and Horner syndrome. The patients underwent chest radiography to rule out phrenic nerve palsy. A doctor blinded to the groups visited the patients and evaluated pain using a numerical rating scale (NRS; 0, no pain; 10, most severe pain imaginable) up to 48 h from the time of arrival in the recovery room. The patients were given i.v. tramadol 100 mg, up to three times a day when NRS was at least 3 or analgesia was requested. In the case of insufficient analgesia, patients were treated with i.v. ketorolac 30 mg up to 90 mg a day. Individual doses given were recorded.
Statistical analysis The Statistical Package for the Social Sciences (SPSS; 18.0, Chicago, Illinois, USA) was used for statistical analysis. The primary endpoint was the time to the first analgesic request, defined as the interval between SISB and the first administration of analgesic. Secondary outcomes included the number of patients not requiring analgesics, analgesic use, pain scores and incidences of arm weakness, arm numbness and adverse effects for 48 h postoperatively. From our prior experience and that of Cummings et al.,8 we expected a block duration of 10 h with ropivacaine alone, and an 11-h difference between
Eur J Anaesthesiol 2015; 32:650–655 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
652 Woo et al.
the control and treatment groups was considered clinically significant. Therefore, a sample size of 32 patients (a ¼ 0.05, power ¼ 80%) per group was calculated (logrank test). Correction for dropouts suggested n ¼ 36 patients per group. Continuous variables were analysed by analysis of variance or the Kruskal–Wallis test after assessment for normality and are presented as mean SD or as median and interquartile range (IQR) as appropriate. Categorical variables were analysed using the x2 or Fisher exact tests. The time to the first analgesic request was analysed by Kaplan–Meier survival analysis with the logrank test and the Cox proportional hazards model to estimate likelihood ratios adjusted for covariates. The Bonferroni correction was applied for three comparisons against the control group and the corrected P values are presented. The secondary outcomes (number of patients who did not require analgesics, and the incidences of arm weakness, numbness and adverse effects) were analysed using linear-by-linear association x2 test. Tramadol and ketorolac use and pain scores were analysed using the linear regression test after conversion to the van der Waerden normal scores because those data were not normally distributed. A P value less than 0.05 was considered statistically significant.
Results One hundred and fifty-nine patients were assessed for eligibility and 15 were ineligible because of the exclusion criteria or patient refusal; in total, 144 patients were included in the analysis. Figure 1 illustrates the allocation process according to the Consolidated Standards of
Reporting Trials (CONSORT) statement. Baseline covariates were well balanced across the randomised groups (Table 1). Perioperative clinical details such as the preoperative pain score, duration of operation and anaesthesia and type of surgery were distributed evenly among the four groups (Table 2). Dexamethasone significantly (log-rank test P < 0.001) prolonged the duration of analgesia. Kaplan–Meier curves were used to measure the time to the first analgesic request during the first postoperative 48 h. In the control group, the time to first analgesic request was a median (IQR) of 11.0 (8.2 to 14.4) h. Compared with the control group, dexamethasone doses of 2.5, 5 and 7.5 mg resulted in times to first analgesic request of 17.3 (12.2 to 22.0) h (P ¼ 0.005), 24.2 (15.8 to 49.8) h (P < 0.001) and 19.9 (15.5 to 49.6) h (P < 0.001), respectively. A Cox proportional hazards model for the time to the first analgesic request was performed including the following variables: dexamethasone dose, sex, age and type of surgery. None of the variables except dose of dexamethasone was significant (Fig. 2). Table 3 summarises the pain scores and analgesic requirements during the first postoperative 48 h. There was a dose-dependent increase in the number of patients not requiring analgesics for the first postoperative 48 h with dexamethasone (P < 0.001). Likewise, there were dose-dependent reductions in the uses of tramadol (P ¼ 0.003) and ketorolac (P < 0.0001) with dexamethasone. There were no dose-dependent effects on NRS at each time point. The other secondary outcomes are
Fig. 1
Enrolment
Assessed for eligibility (n = 159)
Excluded (n = 159) ♦ Notmeeting inclusion criteria (n = 8) ♦ Declined to participate (n = 7)
Randomised (n = 144)
Allocation Allocated to no addition of dexamethasone (n = 36)
Allocated to addition of dexamethasone 2.5 mg (n = 36)
Allocated to addition of dexamethasone 5 mg (n = 36)
Allocated to addition of dexamethasone 7.5 mg (n = 36)
Follow-up No patients lost to follow-up for the study through postoperative 48h
Analysis Analysed (n = 36)
Analysed (n = 36)
Analysed (n = 36)
Analysed (n = 36)
CONSORT flow chart.
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Dexamethasone dose and interscalene blocks 653
Table 1
Patient characteristics
Age (years) Weight (kg) Sex (male:female) ASA physical status (1 : 2)
Saline 0.9% (n U 36)
Dex 2.5 mg (n U 36)
Dex 5 mg (n U 36)
Dex 7.5 mg (n U 36)
54.4 17.8 66.5 12.1 23 : 13 9 : 27
50.8 16.1 67.8 14.3 22 : 14 18 : 18
54.3 15.0 66.1 10.1 25 : 11 12 : 24
47.3 17.5 74.7 24.4 30 : 6 17 : 19
Values are mean SD or count. The groups were similar in respect of baseline variables. ASA, American Society of Anesthesiologists; Dex, dexamethasone.
summarised in Table 4. There were no significant differences in the incidences of arm weakness, numbness or adverse effects including nausea, vomiting, dizziness, phrenic nerve palsy, Horner syndrome and hoarseness during the study period. During the second postoperative 24 h, arm weakness was observed in one patient who had received dexamethasone 2.5 mg and arm numbness was noted in three patients who had received 5 mg. However, all neurological signs had resolved by the following day. At day 14 of follow-up, no patient reported persistent symptoms such as weakness, paraesthesiae or numbness of the arm.
Discussion Our results have shown that perineural dexamethasone significantly prolongs the analgesia induced by ropivacaine SISB and that this effect is dose-dependent. Although the most noticeable prolongation of analgesia was observed with dexamethasone 5 mg, there was a significant dose-dependent increase in the number of patients not requiring analgesics with dexamethasone. There was also a beneficial dose-dependent effect on analgesic use. This randomised study was designed to minimise possible biases by using a single anaesthesiologist and surgeon. The types of surgery were also distributed evenly among the groups. Furthermore, a Cox proportional hazards model revealed that the type of surgery did not affect our results. Previous authors have performed SISB using 20 to 40 ml of 0.5 to 0.75% ropivacaine or bupivacaine for SISB,7–11 but we used 12 ml of ropivacaine 0.5% (60 mg) for SISB. In the study by Desmet et al.,7 SISB was performed with 30 ml of ropivacaine 0.5% followed by general anaesthesia for ASS. They reported a high incidence of Horner syndrome and hoarseness, although the duration of analgesia and the amount of analgesics used were comparable with our results using a lower volume of Table 2
ropivacaine 0.5%. No patient experienced Horner syndrome or hoarseness in our study. We evaluated doses of perineural dexamethasone up to 7.5 mg. In a previous study using SISB as surgical anaesthesia for ASS, Tandoc et al.9 used 40 ml of bupivacaine 0.5%. They found that doses of 4 and 8 mg of perineural dexamethasone prolonged sensory blocks to 21.6 2.4 h and 25.2 1.9 h, respectively, although these were not significantly different. This result is comparable with our study, which showed an analgesic duration of 24.2 (15.8 to 49.8) h with dexamethasone 5 mg and no further additional benefit with 7.5 mg. The mechanisms behind the beneficial effect of dexamethasone and the route of administration remain to be determined. It has been suggested that the effect is mediated by direct blockade of transmission in nociceptive C-fibres, reducing the release of inflammatory mediators and ectopic neuronal discharge, and upregulation of potassium channels.14–16 Recently, the route of dexamethasone administration has been debated and several studies have reported that intravenous dexamethasone can produce opioid-sparing effects under various situations,17 and that there was no difference in the analgesic effect between perineural and systemic administration.7,18,19 This reduces the probability that dexamethasone exerts its action by a direct perineural effect. However, some evidence has suggested that dexamethasone exerts its activity via a perineural effect. Whereas a meta-analysis of 24 randomised trials suggested that a single dose of intravenous dexamethasone at doses less than 0.1 mg kg1 did not produce an opioid-sparing effect,17 even 2.5 mg of perineural dexamethasone prolonged the length of the sensory block in our study. Kawanishi et al.11 demonstrated that 4 mg of perineural dexamethasone as an adjuvant for SISB using 20 ml ropivacaine 0.75% produced a significant advantage over intravenous dexamethasone administration.
Perioperative data
Preoperative pain (NRS) Operation time (min) Anaesthetic time (min) Surgery, n (%) Rotator cuff repair Labral repair Arthroscopic capsular release Greater tuberosity reconstruction
Saline 0.9% (n U 36)
Dex 2.5 mg (n U 36)
Dex 5 mg (n U 36)
Dex 7.5 mg (n U 36)
2.1 1.4 81.3 30.7 131.4 35.7
2.3 1.5 79.2 30.8 131.5 34.4
2.1 1.5 87.9 49.4 138.6 52.1
2.8 1.7 79.3 35.34 130.8 39.6
29 7 0 0
(80.6) (19.4) (0) (0)
26 9 1 0
(72.2) (25.0) (2.8) (0)
24 8 1 3
(66.7) (22.2) (2.8) (8.3)
26 10 0 0
(80.6) (27.8) (0) (0)
Values are mean SD or count (%). Data were similar among groups. Dex, dexamethasone; NRS, numerical rating scale.
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654 Woo et al.
Fig. 2
Proportion of patients not requesting analgesia
1.0
0.9% saline Dex 2.5 mg Dex 5 mg Dex 7.5 mg
0.8
0.6
* *
0.4
* 0.2
0.0 0
500
1000
1500
2000
2500
3000
Time to first analgesic request (min) Kaplan–Meier survival plot. Dex, dexamethasone. Corrected P < 0.05 compared with control group (0.9% saline).
There have been concerns about the use of perineural dexamethasone. Because trials require large sample sizes to come to reliable conclusions about safety in respect of extremely rare events, there is no alternative but to rely on the results of experimental studies. Several animal experiments have demonstrated no significant long-term adverse effects.20,21 Moreover, epidural injections of corticosteroids have long been used to treat radiculopathy and, to date, no clinical trial has reported any neurological complications attributed to dexamethasone.16 Neural injury can also be related to needle-induced direct trauma. In our study, we performed SISB under ultrasound guidance using the in-plane approach to minimise the risk of trauma to nerves. The appropriate spread of local anaesthetic within the sheath of the interscalene brachial plexus was ascertained during administration. Thus, local anaesthetics were allowed to spread with sufficient perfusion throughout the brachial plexus and SISB was achieved successfully in all patients without persistent neurological complications.
Table 3
There are several limitations of the present study. First, our sample sizes are to too small to discuss clinical or statistically significant differences between different dexamethasone doses. This study was also not designed to find the optimal dose of dexamethasone. Our results only confirm a significant beneficial dose-dependency with dexamethasone. Second, we focused on outcomes during the acute postoperative period and did not specifically evaluate long-term complication profiles. However, on the day of discharge and on day 14 of follow-up, no patient reported neurological complications. Third, we did not analyse changes in the postoperative blood glucose concentration. One study showed that the elevation of blood glucose after SISB using dexamethasone 10 mg was statistically significant but clinically irrelevant. Fourth, given the extremely low rate of persistent neurological complications and safety concerns with perineural dexamethasone use, further studies are warranted to clarify dexamethasone administration as an adjuvant.
Pain intensity and analgesic requirements for the first postoperative 48 h Saline 0.9% (n U 36)
Patients not requiring analgesicsM Tramadol use (n)MM Ketorolac use (n)MM NRS at 6 h NRS at 12 h NRS at 24 h NRS at 48 h
1 2 2 1 3 2 1
(2.8%) (1 to 3) (1 to 3) (0 to 3) (1 to 4) (1 to 3) (0 to 2)
Dex 2.5 mg (n U 36) 8 1 1 0 1 1 0
(22.2%) (0 to 1) (0 to 1) (0 to 1) (0 to 2) (0 to 3) (0 to 1)
Dex 5 mg (n U 36) 14 1 1 0 1 2.5 0
(38.9%) (0 to 1) (0 to 1) (0 to 1) (0 to 3) (0.25 to 5) (0 to 2)
Dex 7.5 mg (n U 36) 12 1 1 0 1 1.5 0
(33.3%) (0 to 1) (0 to 1) (0 to 2) (0 to 2) (1 to 4) (0 to 1)
Values are median (IQR) or count (percentage). There were no significant differences among groups. Data were similar among groups. Dex, dexamethasone; NRS, numerical rating scale. M P < 0.001 by linear-by-linear association x2 test. MM P < 0.05 by linear regression analysis using the van der Waerden normal scores.
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Dexamethasone dose and interscalene blocks 655
Table 4
Secondary outcome variables Saline 0.9% (n U 36)
Dex 2.5 mg (n U 36)
Dex 5 mg (n U 36)
Dex 7.5 mg (n U 36)
8 0
12 1
14 0
15 0
18 0 6 0 2 1 0 0 0
15 0 3 0 1 2 0 0 0
18 3 8 0 2 1 0 0 0
22 0 8 1 2 4 0 0 0
Arm weakness 0 to 24 h 24 to 48 h Arm numbness 0 to 24 h 24 to 48 h Nausea Vomiting Dizziness Phrenic nerve palsy Horner syndrome Hoarseness Dyspnoea
Values are counts. Dex, dexamethasone. There were no significant differences by x2 or Fisher exact tests and no significant dose-dependent trend.
In conclusion, we have shown that perineural dexamethasone has significant beneficial dose-dependent effects on the time to the first analgesic request, the number of patients not requiring analgesics and analgesic use during the first postoperative 48 h when added to 12 ml ropivacaine 0.5% for SISB in ASS.
Acknowledgements relating to this article
8
9
10
11
Assistance with the study: none. Financial support and sponsorship: none.
12
Conflict of interest: none. Presentation: preliminary data from this study were presented at the annual meeting of the European Society of Anaesthesiology, May 2014, Stockholm.
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