THE EFFECT OF DEXAMETHASONE ON THE DURATION OF
INTERSCALENE NERVE BLOCKS WITH ROPIVACAINE OR BUPIVACAINE
by
KENNETH C. CUMMINGS III, M.D.
Submitted in partial fulfillment of the requirements
For the degree of Master of Science
Clinical Research Scholars Program
CASE WESTERN RESERVE UNIVERSITY
May, 2011 CASE WESTERN RESERVE UNIVERSITY
SCHOOL OF GRADUATE STUDIES
We hereby approve the thesis/dissertation of
Kenneth C. Cummings III, M.D.
candidate for the Master of Science degree *.
Randall Cebul, M.D. (signed) (chair of the committee)
Daniel Sessler, M.D.
Denise Babineau, Ph.D.
March 3 ,2011 (date)
*We also certify that written approval has been obtained for any proprietary material contained therein. TABLE OF CONTENTS
List of Tables ...... 3 List of Figures ...... 4 Acknowledgments ...... 5 Abstract ...... 6 Hypotheses ...... 8 Objectives ...... 8 Background and Significance ...... 9 Introduction: Interscalene Brachial Plexus Blocks ...... 9 Prolonging Analgesia from Interscalene Blocks: Catheter Techniques ...... 10 Prolonging Analgesia from Interscalene Blocks: Adjuvant Drugs ...... 11 Prolonging Analgesia from Interscalene Blocks: Glucocorticoids ...... 12 Differences between Local Anesthetics ...... 13 Materials and Methods ...... 16 Design and Setting ...... 16 Participants ...... 16 Intervention ...... 17 Data Analysis: Primary Outcome ...... 20 Data Analysis: Secondary Outcomes ...... 21 Data Analysis: Subgroups ...... 21 Sample Size Considerations ...... 21 Results ...... 24 Primary Outcome ...... 27 Secondary Outcomes ...... 28 Subgroup Analyses ...... 30 Open versus Arthroscopic Procedures ...... 30 Study Site ...... 31 Ethnicity ...... 32 Safety ...... 32 Discussion ...... 34 Appendix ...... 40 Appendix 1A—Open Procedures: Pain Scores at Rest and with Movement ...... 40 Appendix 1B—Arthroscopic Procedures: Pain Scores at Rest and with Movement ...... 40 Appendix 2A—Euclid Hospital: Pain Scores at Rest and with Movement ...... 41 Appendix 2B—Hillcrest Hospital: Pain Scores at Rest and with Movement ...... 41 Appendix 2C—Strongsville ASC: Pain Scores at Rest and with Movement ...... 42 Bibliography ...... 43
2
LIST OF TABLES
Table 1—Opioid Equivalent Doses ...... 19
Table 2—Summary of patient characteristics by treatment group ...... 26
Table 3—Total Three-Day Opioid Consumption in Oral Oxycodone Equivalents ...... 30
Table 4—Median Time to First Analgesic Request and Opioid Use by Procedure ...... 30
Table 5—Median Time to First Analgesic Request and Opioid Use by Study Site ...... 31
3
LIST OF FIGURES
Figure 1—Chemical Structures of Ropivacaine and Bupivacaine ...... 14
Figure 2—Stopping Boundaries for Interaction ...... 24
Figure 3—CONSORT Study Flow Diagram ...... 25
Figure 4—Time to First Opioid Analgesic Use ...... 27
Figure 5—Time to Noticeable Increase in Pain ...... 28
Figure 6—VRS Pain Scores at Rest and with Movement ...... 29
4
ACKNOWLEDGMENTS
The author thanks Edward Mascha, Ph.D. for assistance with the sample size calculations and design of the data analysis plan and Jarrod Dalton, M.A. and Linda
Cummings, M.D, M.S. for assistance with the data analysis and statistical programming. The author also thanks the Committee members for their advice and assistance.
5
The Effect of Dexamethasone on the Duration of Interscalene Nerve Blocks with
Ropivacaine or Bupivacaine
Abstract
by
KENNETH C. CUMMINGS III, M.D.
Background: Single-injection interscalene blocks for shoulder surgery are effective but
time-limited. Adjuncts such as dexamethasone may help. This study tested the hypothesis
that adding dexamethasone significantly prolongs the duration of ropivacaine and bupivacaine analgesia, and that the effect differs between the two local anesthetics.
Methods: At 3 centers in the Cleveland Clinic, 218 patients undergoing shoulder procedures
with interscalene blocks were randomized to 4 groups: 30 ml ropivacaine or bupivacaine
0.5% with or without dexamethasone 8mg. The primary outcome was time to first analgesic
request. Kaplan-Meier curves and Cox proportional hazard models were used to compare
groups.
Results: Dexamethasone significantly prolonged analgesia from both ropivacaine (Kaplan-
Meier curve estimated median [interquartile range] 11.8 [9.7, 13.8] versus 22.2 [18.0, 28.6] hours) and bupivacaine (14.8 [11.8, 18.1] and 22.4 [20.5, 29.3] hours). This effect was stronger in ropivacaine than bupivacaine.
6
Conclusions: Dexamethasone prolongs analgesia from blocks using ropivacaine or bupivacaine, with the effect stronger with ropivacaine.
7
HYPOTHESES
1. Dexamethasone prolongs the analgesic effect of interscalene brachial plexus blocks.
2. This prolongation differs depending on whether dexamethasone is added to bupivacaine
or ropivacaine.
OBJECTIVES
Primary Objectives
1. To determine the duration of analgesia (time to first analgesic request) after interscalene
blocks when dexamethasone is added to bupivacaine or ropivacaine for patients
undergoing moderately- to severely-painful shoulder procedures.
2. To evaluate any difference in effect of dexamethasone when added to bupivacaine versus
ropivacaine.
Secondary Objectives
1. To evaluate the effect of adding dexamethasone to local anesthetics on postoperative
opioid requirements.
2. To evaluate any difference in postoperative pain scores after interscalene block due to
adding dexamethasone.
3. To determine any increase in intermediate-term (2-week) complications of interscalene
blocks due to adding dexamethasone.
8
BACKGROUND AND SIGNIFICANCE
Introduction: Interscalene Brachial Plexus Blocks
Pain after orthopedic surgery can be intense.1 In particular, managing pain after
shoulder procedures poses a challenge to both anesthesiologists and orthopedic surgeons. In
an effort to improve analgesia and facilitate mobilization, regional anesthesia in the form of
an interscalene approach to the brachial plexus is often used either as an adjunct to general
anesthesia or as the primary anesthetic. The brachial plexus of nerves arises from the ventral
rami of C5 to T1 (with variable contributions from C4 and T2) and travels between the
anterior and middle scalene muscles, ultimately providing sensory and motor innervation to
the shoulder, arm, and hand. The upper elements of the plexus (innervating the shoulder and
part of the arm) are more superficial and are readily accessible for deposition of local
anesthetic in the interscalene area.2
Although associated with complications such as plexus injury, unintended spinal or
epidural anesthesia, or intravascular injection, the actual rate of severe acute or long-term complications is only 0.4%.3 Use of an interscalene block as the primary anesthetic increases
the proportion of patients suitable for PACU bypass and decreases immediate postoperative
pain.4 However, the improved analgesia is short-lived: the block has not been shown to
improve pain scores beyond 24 hours postoperatively.
9
Prolonging Analgesia from Interscalene Blocks: Catheter Techniques
Multiple studies have evaluated perineural catheters as a means to provide
continuous brachial plexus analgesia for both inpatient5-6 and outpatient4 situations. Such
catheters are placed in the perioperative period and then left in place for several days to
provide a continuous supply of local anesthetic to the nerves. These techniques, however,
pose logistical difficulties such as secondary block failure (pain after the initial bolus of
medication diffuses), disconnection, and equipment troubleshooting.7-8 Furthermore,
outpatient use of indwelling peripheral nerve catheters is potentially associated with
infectious complications and unrecognized local anesthetic toxicity, although neither concern has yet been substantiated.
In addition to these safety and convenience issues, there are significant cost differences between single-injection blocks and continuous catheter techniques. For example, the average acquisition cost for 30 ml of 0.5% ropivacaine (Naropin©, APP
Pharmaceuticals, Schaumburg, IL) used for a single-injection block is approximately $10
(personal communication, Department of Pharmacy, Hillcrest Hospital, Mayfield Heights,
OH). For the most commonly-used ambulatory infusion pump (On-Q with Select-A-Flow and
ONDEMAND©, I-Flow Corporation, Lake Forest, CA) filled with 0.2% ropivacaine, the
acquisition cost is roughly $500. Patient charges and reimbursement will vary, so catheters
may make financial sense for a particular institution, but the societal economic benefit of a
simpler, less expensive regimen is clear.
10
Prolonging Analgesia from Interscalene Blocks: Adjuvant Drugs
Patients undergoing shoulder procedures with single-injection interscalene blocks are
frequently hospitalized overnight due to inadequate pain relief after resolution of their
blocks. For 0.5% ropivacaine or bupivacaine, the usual local anesthetics, previous studies
report an average analgesic duration of 11 hours without epinephrine9 and approximately 12
hours with epinephrine.10 Consequently, a method of prolonging analgesia from a brachial
plexus block without the extra cost and logistical difficulties of indwelling catheters would
benefit both patients and their caregivers. One promising approach is use of adjuvant drugs
that prolong block duration when added to the local anesthetic.
Many drugs have been studied as adjuvants for single-injection regional anesthetic
techniques. Epinephrine is commonly used as a marker of intravascular injection, but has
minimal effect on the duration of analgesia of long-acting local anesthetics.10 In addition to
epinephrine, drugs including clonidine, opioids, and ketamine have been evaluated for their
effects on anesthesia and analgesia. Results have conflicted depending on the drug used and
the choice of local anesthetic.
Clonidine, an α2 adrenergic agonist, has shown inconsistent results in trials using
axillary brachial plexus blocks. In two trials, it prolonged anesthesia from lidocaine11 as well as mepivacaine and bupivacaine, but not ropivacaine.12 A separate study, however, contradicts these results, showing no benefit with bupivacaine or levobupivacaine.13 Any potential benefit from clonidine must also be weighed against its sedative and hypotensive effects when absorbed.
Due to their systemic analgesic effects, opioids have also been evaluated for effectiveness when mixed with local anesthetics. Fentanyl, a synthetic opioid, has been
11
shown to prolong analgesia from axillary brachial plexus blocks with lidocaine and
bupivacaine.14-15 In contrast, other investigators found no benefit with ropivacaine.16
Buprenorphine, an opioid agonist-antagonist, has been demonstrated to modestly prolong analgesia after axillary blocks with a mixture of local anesthetics17-18 as well as sciatic nerve
blocks using bupivacaine with epinephrine.19 Opioids also have the potential for systemic effects (sedation, respiratory depression, nausea) after absorption of the local anesthetic mixture.
Ketamine is a phencyclidine derivative used as a sedative and analgesic. It has been shown to inhibit axonal conduction when injected intrathecally,20-21 thus providing rationale
for its study in peripheral nerve blocks. Limited data support its use in axillary brachial
plexus blocks22 but not local wound infiltration (“field block”).23 Ketamine also has systemic
effects when absorbed (sedation, dysphoria) and its toxicity to nervous tissue is a subject of
concern.24
Prolonging Analgesia from Interscalene Blocks: Glucocorticoids
Because of the limited efficacy or questionable toxicity of the previously-studied
drugs, some investigators have begun to evaluate glucocorticoids as adjuvants for regional
anesthesia. Known for their anti-inflammatory, analgesic, immunosuppressive, and
antiemetic properties, these corticosteroids exert their effects by inhibition of phospholipase
A2 as well as changes in cell function induced by glucocorticoid receptor activation.
Although these drugs are associated with significant toxicity when administered in large
doses for long periods, the literature suggests that a single perioperative dose of
glucocorticoid is safe.25-26
12
Adding glucocorticoids to local anesthetics for regional anesthesia is an emerging
strategy that has only been evaluated in small trials. One study demonstrated a prolongation
of sensory block from 98 to 242 minutes when dexamethasone 8 mg was added to lidocaine
for axillary blocks.27 Methylprednisolone appears to have similar effects.28 Similar results
were found with supraclavicular blocks when dexamethasone 4-8 mg was added to a mixture
of lidocaine and bupivacaine.29 When added to a single injection of epidural bupivacaine, the
duration of analgesia was increased by a factor of 5.30 Parrington and colleagues31
demonstrated that adding dexamethasone 8 mg to mepivacaine increased the median
duration of supraclavicular blocks from 228 to 332 minutes. Finally, Vieira and colleagues 32
found that adding dexamethasone to a mixture of bupivacaine, epinephrine, and clonidine
increased block duration from 833 to 1457 minutes. The available data, although limited,
thus suggest that combining glucocorticoids with local anesthetics prolongs block duration.
Importantly, however, none of these studies evaluated ropivacaine (or plain bupivacaine) block duration.
Why dexamethasone would prolong regional anesthesia is a subject of much discussion and speculation. Steroids induce some degree of vasoconstriction, so one hypothesis is that it acts in a similar manner to epinephrine by reducing local anesthetic absorption. A more attractive hypothesis holds that dexamethasone may act locally on nociceptive C-fibers (via glucocorticoid receptors) to increase the activity of inhibitory potassium channels, thus decreasing their activity.33-34
Differences between Local Anesthetics
Given the differences seen with other adjuvants (particularly fentanyl and clonidine),
it might not be reasonable to assume that dexamethasone’s effect would be similar with
13
different local anesthetics. Although ropivacaine is commonly used for interscalene blocks,
bupivacaine use is still widespread. Bupivacaine is a racemic mixture of stereoisomers,
whereas ropivacaine is supplied as the pure S(-) isomer. Chemically, however, they are similar
amide-class local anesthetics, differing only in the number of carbon atoms on the n-alkyl-
substituted piperidine ring: bupivacaine has a butyl (4-carbon) group whereas ropivacaine
has a propyl (3-carbon) group (Figure 1).35 This slight difference may in fact be clinically
important, as the decreased lipid solubility of ropivacaine is advanced as an explanation for
its enhanced tendency to block sensory nerve fibers more readily than motor fibers
compared to bupivacaine.
Figure 1—Chemical Structures of Ropivacaine and Bupivacaine
The relative toxicities and potencies of ropivacaine and bupivacaine are the subject
of much debate. In summary, ropivacaine appears to be 10-25 percent less toxic to the
central nervous system (on a per-milligram basis) and roughly 30 percent less cardiotoxic.
Although ropivacaine may be less potent for spinal anesthesia, it appears to be equipotent to
bupivacaine for peripheral nerve blocks.36 Additionally, the dose-response curves for bupivacaine and ropivacaine are not significantly different at clinically-relevant
14
concentrations for peripheral nerve blocks.37 Therefore, in this paradigm, it is reasonable to use identical concentrations of ropivacaine and bupivacaine.
Because no direct comparison has been undertaken (and ropivacaine has not been studied), this study tested the hypothesis that dexamethasone prolongs the analgesic effect of interscalene blocks using ropivacaine or bupivacaine for shoulder surgery and that this effect differs between the two local anesthetics.
15
MATERIALS AND METHODS
Design and Setting
This prospective, randomized, double-blinded, placebo-controlled study was approved by the Cleveland Clinic Institutional Review Board (protocol 08-647) and conducted at Hillcrest and Euclid Hospitals and the Strongsville Ambulatory Surgery Center in the Cleveland Clinic Health System. The trial was registered with ClinicalTrials.gov (#
NCT00801138). A total of 218 patients were enrolled between December, 2008 and
October, 2010 via the preadmission testing centers of the respective facilities.
Participants
Inclusion criteria were patients (age 18-75) undergoing moderately- to severely- painful shoulder procedures (such as rotator cuff repair, capsular shift, shoulder arthroplasty, and subacromial decompression) for which an interscalene block was planned.
Exclusion criteria included patient refusal, contraindication to interscalene block
(severe chronic obstructive pulmonary disease, infection, coagulopathy, contralateral diaphragmatic paralysis), pregnancy, neuropathy of the surgical limb, recent (less than six months) use of glucocorticoids for at least two weeks, and chronic pain requiring daily use of opioid medication (greater than 30 mg/day of oral oxycodone equivalent).
16
Intervention
Patients were randomized to single-injection interscalene blocks with four possible drug combinations:
1) Ropivacaine: 30 ml 0.5% ropivacaine mixed with 2 ml 0.9% saline (placebo)
2) Bupivacaine: 30 ml 0.5% bupivacaine mixed with 2 ml 0.9% saline (placebo)
3) Ropivacaine and steroid: 30 ml 0.5% ropivacaine mixed with dexamethasone 8
mg (2 ml)
4) Bupivacaine and steroid: 30 ml 0.5% bupivacaine mixed with dexamethasone 8
mg (2 ml)
Computer-generated treatment assignments, with random permuted block size, were stratified by clinical site and the invasiveness of the surgical procedure (open vs. arthroscopic). Randomization assignments were stored in sealed, sequentially-numbered opaque envelopes and opened immediately before the blocks were performed.
Demographic (age, gender, comorbidities) and morphometric (height, weight) characteristics of participating patients were recorded. Patients, clinical personnel, and study staff were blinded to group allocation. To maintain blinding, medications were prepared by an experienced assistant uninvolved with the study or care of study patients. All blocks were performed by attending anesthesiologists skilled in the interscalene approach. The choice of block technique (nerve stimulator and/or ultrasound) was left to the discretion of the attending anesthesiologist. Both block techniques used 50-mm-long insulated needles
(Stimuplex A, B Braun, Melsungen, Germany). The ultrasound technique consisted of an in- plane posterior approach at the level of the cricoid cartilage. The nerve roots/trunks were identified as hypoechoic structures between the anterior and middle scalene muscles. Local
17
anesthetic was injected and needle position readjusted as necessary to ensure appropriate
spread. The nerve stimulation technique used was described by Winnie,38 with muscle
contraction of the deltoid or arm muscles at a stimulating current of <0.4 mA (2 Hz, 0.1 ms
duration) considered evidence of appropriate needle position.
After incremental injection of the designated local anesthetic mixture, patients were
evaluated at 5-minute intervals for 15 minutes for development of sensory and motor block.
Sensory block was assessed by loss of sensation to pinprick over the deltoid muscle. Motor
block was assessed by failure to abduct the shoulder, the so-called “deltoid sign.”39
Per the institutions’ clinical routine, patients were given general anesthesia along with
their interscalene blocks. The type of airway management, antiemetic prophylaxis, and
intraoperative opioid use were left to the discretion of the attending anesthesiologist with the
provision that no other corticosteroids be administered.
The severity of postoperative pain was assessed by a blinded study team member
using a verbal response score (VRS) upon admission to the post-anesthesia care unit
(PACU). Patients reporting pain scores greater than 2 were given intravenous morphine (2
mg) every 5 minutes until comfortable. After discharge from the PACU, supplemental
analgesia for inpatients consisted of acetaminophen 325-650 mg with oxycodone 5-10 mg
orally every 4 hours as needed for a pain VRS greater than 4, administered by the nurse
caring for the patient. Pain unrelieved by oral medication (VRS persistently greater than 4)
was treated with intravenous morphine. Outpatients received a prescription for oral
acetaminophen with oxycodone (or a similar medication according to surgeon preference)
and were instructed to delay administration of analgesics until they felt that their pain warranted medication.
18
A blinded observer interviewed patients each morning for three days postoperatively, either in the hospital or by telephone. Subjects were given a medication diary to record the required data. Data collected included time of block duration (the primary outcome; defined as time from onset of sensory block to first administration of supplemental analgesic medication after PACU discharge), as well as secondary outcomes: time to a significant increase in shoulder discomfort, maximum VRS with rest and movement, and total three-day opioid consumption. The time to initial analgesic use was determined from the medical record for inpatients and by patient report for those already discharged. The times and VRS scores for secondary outcomes were based on patient reporting of the corresponding events at the daily interview. A member of the study staff contacted patients at 14 days postoperatively to assess for any late or persistent complications such as residual sensory or motor block. Total opioid doses were converted to oral oxycodone equivalents according to conversion rates derived from the American Pain Society (Table 1).40
Table 1—Opioid Equivalent Doses
Drug Oral Dose (mg) Parenteral Dose (mg)
Morphine 30 10 Hydromorphone 7.5 2 Oxycodone 20 ‐ Methadone 10 5 Hydrocodone 30 ‐ Meperidine 300 75 Codeine 200 ‐ Fentanyl ‐ 0.1
19
Data Analysis: Primary Outcome
The primary outcome measure was duration of analgesia, defined as the interval between the onset of sensory block and the initial post-PACU use of opioid analgesia for surgical site pain. Patients who retained deltoid sensation were deemed to have failed blocks, but were analyzed in their assigned groups according to intention-to-treat principles
(specifically, coded as having the outcome at a time of 0 hours). The duration of analgesia
(defined as time from onset of sensory block to first use of opioid analgesia) was analyzed by
Kaplan-Meier curves (compared via log-rank tests) and Cox proportional hazards regression
(stratified by clinical site). An interaction term between dexamethasone and the type of local anesthetic was incorporated into the Cox model to investigate if the effect of dexamethasone on duration of analgesia differed by type of local anesthetic and was assessed using a Wald test in the stratified Cox model.
To maintain an overall 0.10 significance level for detecting an interaction, the significance levels for 6 interim analyses were adjusted for the alpha spent during the interim analysis (see sample size calculations). If the interaction between dexamethasone and type of anesthetic was statistically significant at any of the interim analyses, a Bonferroni correction was applied for the two multiple comparisons of the main effects (steroid effect within each local anesthetic). At the third interim analysis at which the trial was stopped, these adjustments led to a significance level for the main effects (dexamethasone within each local anesthetic) of 0.002175 and for the interaction term 0.0087.
20
Data Analysis: Secondary Outcomes
Secondary outcomes included time to a noticeable increase in shoulder discomfort, maximum VRS pain scores with rest and movement on postoperative days 1, 2, and 3, and total three-day opioid consumption (in oral oxycodone equivalents). Kaplan-Meier curves and unpaired t-tests or Wilcoxon rank-sum tests were used as appropriate. Group distributions of continuous variables were assessed visually using histograms.
Data Analysis: Subgroups
In a post-hoc analysis, the primary outcome of block duration and the secondary outcomes of maximum VRS pain scores and opioid consumption were analyzed by the invasiveness of the procedure (open versus arthroscopic), by clinical site, and by ethnicity.
Statistical testing was not valid due to the multiple subgroups and small sample sizes.
SAS statistical software version 9.2 (SAS Institute, Cary, NC, USA) and R software version 2.11.1 (The R Foundation for Statistical Computing, Vienna, Austria) were used for all statistical analyses.
Sample Size Considerations
Because almost all patients require opioid analgesics after shoulder procedures, sample size estimation assumed no censoring of block durations. In summary, the study was designed to have 90% power to detect clinically important interactions and main effects for the primary outcome of block duration of 3 hours or more. With the planned interim
21
analyses (see below), the expected sample size under the alternative hypothesis (interaction
between dexamethasone and type of anesthetic present) ranged between 73 and 436.
More specifically, Casati7 observed a mean (SD) block duration for ropivacaine 0.5%
of 11.1 (5) hours and bupivacaine 0.5% of 10.9 (3.9) hours both for 15 patients. To be
conservative, a SD of 5 hours was assumed. Based on the data from Casati, et al. and clinical
experience, we hypothesize mean block durations of 17 and 11 hours for ropivacaine
patients with and without dexamethasone, and 20 and 11 hours for bupivacaine patients with
and without dexamethasone, respectively. Under this scenario, the dexamethasone effect (vs.
placebo) would be 6 hours for those receiving ropivacaine and 9 hours for those receiving
bupivacaine, for a difference of 3 hours. In fact, regardless of the actual means, the study
was powered to be able to detect an interaction effect as small as 3 hours.
Adjusting for interim analyses (see below), a maximum of 436 patients at the 0.10
significance level of would be needed to detect an interaction of 3 hours or more between
the two factors with 90% power. A significance level of 0.10 was chosen due to the lower
power to detect interactions relative to main effects. Note that if the test for interaction is
non-significant, this sample size would also provide sufficient power to test the main effect of dexamethasone. In the case of a significant interaction, 2 planned multiple comparisons
(e.g. dexamethasone vs. saline for each type of anesthetic) were performed assuming a
Bonferroni corrected significance level; this sample size (i.e. 73 - 436) also provided ample
power to detect a difference of 3 hours or more in block duration for each of the 2 planned
multiple comparisons.
Six interim analyses were planned to occur at sample sizes of 73, 145, 218, 290, 363
and a final analysis, if necessary, at N=436. Because of a fairly small increase in sample size
22
relative to the number of interim analyses, six were chosen to facilitate early stopping of the
trial. For the test for interaction, stopping boundaries for efficacy (futility) at looks 1-6
respectively were P≤ 0.0018 (>0.9861), P≤ 0.0039 (>0.9556), P≤ 0.0087 (P>0.8534), P≤
0.0191 (P>0.5622), P≤ 0.0411 (P>0.2499) and P≤ 0.0869 (P>0.0869). For the 2 multiple
comparisons of dexamethasone vs. saline for each type of anesthetic, stopping boundaries
for efficacy (futility) at looks 1-6 respectively were P0.0004 (>0.9804), P0.0009 (>0.9120),
P0.0022 (>0.6408), P0.0045 (>0.2632), P0.0096 (P>0.0853), and P0.0202 (P>0.0202).
These boundaries were constructed using the gamma spending approach of Hwang,
et al,41 with gamma parameters of -4 for efficacy and -2 for futility. The gamma parameter describes the rate at which error is spent, with higher numbers indicating faster spending.
The gamma parameter of -4 approximates the O’Brien-Fleming-type boundaries of the Lan-
DeMets method for type I error spending with slightly lower initial stringency. The parameter of -2 was chosen for futility to more aggressively spend type II error which would facilitate earlier stopping if no treatment effect were likely.
The above calculations were made using PROC POWER in SAS statistical software,
Cary NC, and East software, Cytel Corporation, Cambridge, MA.
23
RESULTS
Enrollment began in December 2008. At the third interim analysis (October 2010,
N=218), the efficacy boundary for interaction between dexamethasone and the type of
anesthetic was crossed (Figure 2; Wald test Z = 2.97, P ≤ 0.0087). In light of this, the trial’s
Executive Committee stopped the study.
Figure 2—Stopping Boundaries for Interaction Crosses indicate the test statistic for the interaction between steroid and local anesthetic at each interim analysis
Figure 3 details the patient flow through the study. Baseline covariates were well-
balanced across the groups (Table 2). Seven patients did not have the primary outcome
(opioid use) and were right-censored at 72 hours in the analysis. They were evenly
distributed across the randomized groups.
24
Figure 3—CONSORT Study Flow Diagram
25
Table 2—Summary of patient characteristics by treatment group Data are presented as percent or median [interquartile range]. Characteristic Level Ropivacaine Bupivacaine Ropivacaine+Dex Bupivacaine+Dex
n=54 n=56 n=54 n=54 Clinical Site Euclid (%) 50 50 48 46 Hillcrest (%) 11 14 15 17 Strongsville (%) 39 36 37 37
Age (yr) 55 [44,65] 60 [51,68] 59 [49,68] 58 [53,64]
Body Mass Index 29 [26,34] 29 [26,33] 29 [25,34] 28 [26,32] (kg/m2)
Gender Female (%) 39 34 39 41 Male (%) 61 66 61 59
ASA 2 [2,3] 2 [2,3] 2 [2,2] 2 [2,3] Classification
Ethnicity Caucasian (%) 89 98 96 91
Procedure Arthroscopic (%) 43 41 44 41 Type
Procedure Rotator Cuff (%) 54 55 54 61 Arthroplasty (%) 17 21 20 22 Other (%) 30 23 26 17
Failed Block 4 4 5 4 (%)
No opioid 2 5 5 0 used (%)
Ultrasound‐Guided (%) 69 69 72 69 Nerve Stimulator Used 34 30 33 39 (%)
26
Primary Outcome
Dexamethasone significantly prolonged the median duration of analgesia (estimated from the Kaplan-Meier curves) of both ropivacaine (median [interquartile range] 11.8 [9.7,
13.8] versus 22.2 [18.0, 28.6] hours, log-rank test P < 0.001, interim analysis-adjusted significance level of 0.002175) and bupivacaine (14.8 [11.8, 18.1] versus 22.4 [20.5, 29.3] hours, log-rank test P < 0.001, Figure 4).
Figure 4—Time to First Opioid Analgesic Use Data presented as Kaplan‐Meier survival curves; shaded areas represent adjusted 95% pointwise confidence intervals.
Based on the stratified Cox model for time to first opioid use, the block resolution
(hazard) rate among patients given ropivacaine with dexamethasone was 0.17 times (95% CI
0.08, 0.39) that among patients given ropivacaine alone. For bupivacaine, the block resolution rate in patients given dexamethasone was 0.44 times (95% CI 0.23, 0.83) that of patients receiving bupivacaine alone. The effect of dexamethasone in prolonging block duration was significantly stronger in ropivacaine versus bupivacaine (interaction term Wald test P=0.0029 at an interim-analysis adjusted significance level of 0.0087).
27
An analysis of scaled Schoenfeld residuals (correlation of a predictor with time) and visual inspection of complementary log-log survival plots did not identify any significant violations of the proportional hazards assumption in the Cox models. Additionally, removing influential observations (defined as a standardized DFBETA greater than 0.4) did not affect the model hazard ratio estimates or change the result of the Wald test for interaction.
Secondary Outcomes
Consistent with its effect on the primary outcome of first opioid use, dexamethasone significantly prolonged the length of time until the patients’ first report of surgical site pain
(Figure 5). For ropivacaine, the median time [IQR] to surgical site pain (estimated from the
Kaplan-Meier curves) was 11.9 [9.2, 13.8] hours without dexamethasone and 22.3 [18.0, 27.2] hours with dexamethasone (log-rank test P < 0.001). The corresponding times for bupivacaine were 14.7 [13.4, 17.9] and 25.7 [21.7, 29.2] hours (log-rank test P < 0.001).
Figure 5—Time to Noticeable Increase in Pain Data presented as Kaplan‐Meier survival curves; shaded areas represent adjusted 95% pointwise confidence intervals.
28
Median maximum VRS pain scores at rest (shown in Figure 6) were significantly lower in the bupivacaine plus dexamethasone group compared to saline on postoperative day
1 (3 versus 5, Wilcoxon rank-sum test P < 0.001 at a significance level of 0.025 adjusting for the two comparisons within each day), but not in the ropivacaine groups. The only other significant difference was on postoperative day 3 in the bupivacaine group: the dexamethasone group had a significantly higher maximum VRS pain score than saline
(median 4 versus 2, P = 0.014).
The median maximum VRS pain scores with movement on postoperative day 1
(also shown in Figure 6) were significantly lower in both the ropivacaine plus dexamethasone
(5 versus 7, P=0.005) and bupivacaine plus dexamethasone groups (4 versus 5.5, P=0.01) compared to saline. There were no significant differences on postoperative days 2 and 3.
Figure 6—VRS Pain Scores at Rest and with Movement Solid horizontal lines represent medians, boxes are interquartile range, whiskers extend to the range of the data.
29
Total three-day opioid consumption was obtained from all patients. Opioid consumption was not significantly different between the randomized groups (Table 3).
Table 3—Total Three‐Day Opioid Consumption in Oral Oxycodone Equivalents (mg)
Group Median P‐Value* [Interquartile Range] Ropivacaine/Dexamethasone 79 [45.2, 100] 0.29 Ropivacaine/Saline 75 [45.2, 152.5] Bupivacaine/Dexamethasone 60 [46.7, 105.2] 0.15 Bupivacaine/Saline 85 [51.3, 117.6] *P‐values from Wilcoxon rank‐sum test. Adjusted significance level=0.025.
Subgroup Analyses
Open versus Arthroscopic Procedures
Comparing open versus arthroscopic procedures, the difference in median time to first analgesic request between those with and without dexamethasone is similar and comparable to the overall results (Table 4). Opioid consumption tended to be lower in the arthroscopic groups. Table 4 also details the opioid consumption of each subgroup.
Table 4—Median Time to First Analgesic Request and 3‐Day Opioid Consumption by Procedure Times estimated from Kaplan‐Meier Curves Procedure Anesthetic Dexamethasone Time to First Analgesic Oxycodone Consumption (Yes/No) (median [IQR], hours) (median [IQR], mg) Yes (n=30) 21.9 [18.3, 28.3] 80 [55, 97.5] Ropivacaine No (n=31) 11.3 [10.7, 13.8] 145 [67.3, 175.8] Open Yes (n=32) 25.0 [21.3, 29.1] 81 [53.8, 116.3] Bupivacaine No (n=33) 14.8 [14.0, 18.4] 96 [71, 129.1] Yes (n=24) 24.6 [19.3, 27.6] 52.6 [32.5, 98.8] Ropivacaine No (n=23) 11.9 [9.4, 13.8] 47.6 [31.3, 73.8] Arthroscopic Yes (n=22) 25.2 [20.5, 30.2] 55 [35, 60] Bupivacaine No (n=23) 14.7 [11.3, 16.8] 50 [40, 95]
30
Maximum VRS pain scores among open and arthroscopic procedures are consistent with the overall results. Appendix 1A and 1B display maximum VRS pain scores at rest and with movement comparing open versus arthroscopic procedures.
Study Site
The difference in median time to first opioid request between those with and without dexamethasone was similar among all three clinical sites (Table 5). Total three-day
opioid consumption tended to be higher at Euclid hospital. Table 5 also details opioid
consumption by site.
Table 5—Median Time to First Analgesic Request and Three‐Day Opioid Consumption by Study Site Times estimated from Kaplan‐Meier curves Site Anesthetic Dexamethasone Median time [IQR] Oxycodone Consumption (Yes/No) (hours) (Median [IQR], mg) Yes (n=26) 21.9 [18.3, 29.2] 79.5 [45, 111.3] Ropivacaine No (n=27) 12.3 [9.7, 13.6] 153 [70.5, 182] Euclid Yes (n=25) 22.9 [21.3, 28.1] 90 [70, 120] Bupivacaine No (n=28) 14.8 [14, 18.4] 120 [82.5, 136.2] Yes (n=8) 22.4 [21.8, 26.8] 72.5 [53.75, 88.5] Ropivacaine No (n=6) 11.0 [9.8, 15.2] 52.5 [46.25, 88.75] Hillcrest Yes (n=9) 27.1 [17.6, 30.9] 50 [45, 75] Bupivacaine No (n=8) 14.7 [10.8, 15] 85.1 [63.8, 99.6] Yes (n=20) 23.4 [15.4, 27.6] 72 [33.8, 98.8] Ropivacaine No (n=21) 11.9 [9.9, 13.9] 55 [27.5, 76.3] Strongsville Yes (n=20) 25.2 [22.3, 30.4] 55 [35, 60] Bupivacaine No (n=20) 14.9 [11.6, 18.0] 50 [35, 75]
Maximum VRS pain scores analyzed by center were also consistent with the main
analysis, namely that pain scores tended to be lower in the dexamethasone groups on
postoperative day 1 and perhaps higher on postoperative day 3. Appendices 2A-2C show
maximum VRS pain scores at rest and with movement at the three study centers.
31
Ethnicity
Removing the small number of non-Caucasian (primarily African-American) patients
(n=14) from the study sample did not appreciably change the primary outcome of time to first analgesic use (Kaplan-Meier curve estimates median 11.9 [19.9, 13.6] hours versus 21.9
[18.3, 27.6] hours for ropivacaine and 14.8 [12.8, 18.1] hours versus 25.7 [21.8, 29.4] hours for bupivacaine; log-rank test P < 0.001 for both Kaplan-Meier curve comparisons).
Total opioid consumption also did not significantly differ between groups when only
Caucasian patients were analyzed: 81.4 [50, 154] versus 79 [45, 100] mg for ropivacaine with and without dexamethasone, respectively (Wilcoxon rank-sum test P=0.1) and 60 [49.2,
101.3] versus 87.5 [53.8, 120.4] mg for bupivacaine with and without dexamethasone, respectively (Wilcoxon rank-sum test P=0.1).
Maximum VRS pain scores among Caucasians were also consistent with the entire sample. At an adjusted significance level of 0.025 (for two comparisons within each day), median VRS pain with movement on postoperative day 1 in the ropivacaine groups was 5 versus 7 for dexamethasone and saline, respectively (Wilcoxon rank-sum test P=0.002). For bupivacaine, median postoperative day 1 scores at rest were 4 versus 5 (P<0.001) for dexamethasone versus saline and 5 versus 5.5 with movement (P=0.003). There were no other detectable differences at the 0.025 significance level.
Safety
All patients were contacted at 14 days postoperatively. At the 14-day interview, no patient reported persistent numbness, paresthesias, or weakness of the operative limb. There
32
were also no reports of persistent hoarseness, respiratory difficulty, injection site infection, or hematoma.
33
DISCUSSION
This study demonstrates that dexamethasone significantly prolongs the analgesic effect of plain ropivacaine and bupivacaine used as a single-injection interscalene block, and that this effect differs between the two local anesthetics. This finding is generally consistent with previous studies, but direct comparisons are difficult because of the variety of local anesthetic mixtures used, different blocks studied, and different methods of evaluating block duration.
The magnitude of block prolongation we observed is consistent with that observed by Parrington and colleagues when dexamethasone was combined with mepivacaine for supraclavicular blocks.31 Similarly, Vieira and colleagues32 observed that adding dexamethasone to a mixture of bupivacaine, clonidine, and epinephrine increased interscalene block duration from 13.9 to 24.3 hours. Their results, however, must be interpreted in light of the presence of two alpha agonists that were also included in the local anesthetic mixture.
We were unable to demonstrate the multi-fold prolongation of analgesia found in one study of bupivacaine/lidocaine supraclavicular blocks29 and a trial of dexamethasone
added to epidural bupivacaine.30 An exaggerated effect may be due to the small size of those
trials, as the accuracy with which treatment effects are estimated in smaller studies is often low. The balance of the small body of existing literature, however, supports the more modest—but still highly clinically important—benefit observed in this trial.
As would be expected from longer block duration, maximum VRS pain scores
tended to be lower on the first postoperative day. Beyond this time, however, there appeared
34
to be no lasting benefit in terms of lower in pain scores. It is important to note, however,
that the measured pain scores are maximum values over the time period, a fairly coarse
measure of patient experience over time.
The significant (but small) differences in maximum VRS pain scores seen on
postoperative day 3 in the bupivacaine groups and suggested by some of the subgroups is
concerning. It is unlikely that dexamethasone should lead to increased pain, as a significant
amount of literature describes its analgesic effect. One plausible explanation is that the prolonged initial analgesia from interscalene blocks containing dexamethasone led to lower
initial opioid consumption. As the blocks resolved, patients would have received fewer analgesic drugs and might thus experience higher pain scores prior to treatment with systemic opioids. These results, however, should be interpreted cautiously in light of the multiple tests being performed and the fact that the differences, while statistically significant, are small and of questionable clinical importance.
Total opioid consumption over the first 72 hours also did not differ significantly among groups. In the post-hoc analysis by procedure type, however, there appeared to be lower opioid consumption in the arthroscopic groups. This is consistent with the less invasive nature of arthroscopic surgery. When analyzed by site, one clinical location (Euclid
Hospital) appeared to have higher opioid consumption than the others. This most likely reflects differences in the type of procedures performed, with the majority at Euclid
(91/106) being open and thus leading to more postoperative pain. In contrast, arthroscopic procedures were more common at the other sites. This did not, however, lead to clear differences in VRS pain scores between sites.
35
This study is the first to examine the effect of dexamethasone on ropivacaine (or
plain bupivacaine) for interscalene blocks and is by far the largest trial to date examining
adjunctive use of dexamethasone in peripheral nerve blocks. This study was also unique in
that it was designed to detect a modest interaction between dexamethasone and the
particular local anesthetic used: an interaction that proved to be both statistically significant
and clinically important.
Dexamethasone was more effective in prolonging analgesia from interscalene blocks
using ropivacaine than bupivacaine. It is important to note, though, that this effect was
muted by the fact that the median block duration was longer with plain bupivacaine than
ropivacaine (Kaplan-Meier curve estimates 14.8 versus 11.8 hours). Thus although
dexamethasone prolonged the action of ropivacaine more than that of bupivacaine, the
combined effect of dexamethasone and either drug produced nearly the same 22 hours of
analgesia.
Despite the concern surrounding the “off-label” use of perineural adjuvants,42 the safety profile of dexamethasone is promising. No trial has reported neurotoxicity attributable to dexamethasone, although sample sizes to date are insufficient to detect rare outcomes and most studies did not follow patients for weeks after surgery. In this study, with no adverse events out of 108 patients receiving dexamethasone, the 95% confidence interval for
neurotoxicity is (0-3%). Conclusively demonstrating safety with low event rates would
require enormous sample sizes. For example, to demonstrate a doubling of the baseline
complication rate of 0.4% with 90% power, a total sample size of roughly 16,000 patients
would be required; to detect only a 50% increase would require roughly 52,000 patients.
36
Reassuringly, though, animal studies demonstrate no long-term changes in nerve structure or function after local steroid administration.43 From a mechanistic point of view,
toxicity attributed to corticosteroids may in fact be due to the particulate nature44 or vehicle
used45 in different steroid preparations—neither of which applies to the formulation of
dexamethasone (dexamethasone sodium phosphate) used in this study. Additionally,
corticosteroids have a long history of safe use in the epidural space for the treatment of
radicular pain arising from nerve root irritation46 and dexamethasone specifically has been
studied as an adjuvant to epidural local anaesthetics.30 The neurologic risk, if any, of
dexamethasone thus appears to be small. In fact, the use of dexamethasone as an adjunct to
local anesthesia for nerve blocks is discussed in popular textbooks.47-48
Systemic toxicity from a single dose of dexamethasone is also unlikely. It is
effective49 and widely administered intravenously by anesthesiologists for prophylaxis against
postoperative nausea and vomiting. Concerns about steroid-induced hyperglycemia have
been borne out in high-dose intravenous regimens,50 but have not been problematic in
practice (American Society of Anesthesiologists Annual Meeting, October 2009, Abstract
A955).
Perineural glucocorticoids are eventually absorbed and thus may exert systemic
effects. Given intravenously, several steroids have been shown to improve postoperative
pain and reduce postoperative nausea and vomiting.51-54 Any systemic analgesic effect,
however, should be minimal due to slow systemic uptake: a human volunteer trial of
intercostal bupivacaine and dexamethasone microsphere injection resulted in negligible
blood dexamethasone levels.34 Nonetheless, it remains possible (although unlikely) that some
37
or even all of the block prolongation observed could have been obtained by intravenous injection of dexamethasone.
Due to the majority of the patients being discharged before the third postoperative day, our ability to precisely measure opioid consumption by day was limited; telephone followup usually did not provide specific times of administration. Hence, it was only possible to compare 72-hour opioid use between groups. Given the difference in VRS pain scores on postoperative day 1, it is quite plausible that there were initial differences in opioid consumption that were obscured by later opioid use. Although clinically unlikely, one hypothesis to explain the lack of difference in overall opioid use is that patients receiving dexamethasone, although they had less initial pain, had more pain after block resolution and thus required more opioid pain medication over days 2 and 3. A more plausible explanation is that the wide variation in opioid consumption, combined with the relatively small group sizes, led to insufficient power to detect a true difference.
Due to the largely Caucasian ethnicity of the study sample, examining the effect of ethnicity on study outcomes is difficult. Removing non-Caucasian patients from the study sample had little effect on outcomes. Because there may be significant cultural differences in pain expression and/or use of analgesic drugs, studies with varying ethnic composition may be biased towards or away from a null result. Future studies should incorporate ethnicity into their recruitment plans.
The duration of motor block was also not measured, as many patients are discharged home after surgery and resolution of weakness is too subjective to document in the absence of direct evaluation. This would need to be evaluated by a trained observer in future trials.
38
In summary, dexamethasone prolonged analgesia from interscalene blocks using ropivacaine or bupivacaine, with the effect being stronger with ropivacaine. However, block duration was longer with plain bupivacaine than ropivacaine. Thus although dexamethasone prolonged the action of ropivacaine more than that of bupivacaine, the combined effect of dexamethasone and either drug produced nearly the same 22 hours of analgesia. This trial is the largest to date and the first to demonstrate a difference in block prolongation between local anesthetics. Although the toxicity profile of dexamethasone is promising, large studies will be necessary to demonstrate its safety for perineural use.
39
APPENDIX
Appendix 1A—Open Procedures: Maximum VRS Pain Scores at Rest and with Movement Solid horizontal lines represent medians, boxes are interquartile range, whiskers extend to the range of the data.
Appendix 1B—Arthroscopic Procedures: Maximum VRS Pain Scores at Rest and with Movement Solid horizontal lines represent medians, boxes are interquartile range, whiskers extend to the range of the data.
40
Appendix 2A—Euclid Hospital: Maximum VRS Pain Scores at Rest and with Movement Solid horizontal lines represent medians, boxes are interquartile range, whiskers extend to the range of the data.
Appendix 2B—Hillcrest Hospital: Maximum VRS Pain Scores at Rest and with Movement Solid horizontal lines represent medians, boxes are interquartile range, whiskers extend to the range of the data.
41
Appendix 2C—Strongsville ASC: Maximum VRS Pain Scores at Rest and with Movement Solid horizontal lines represent medians, boxes are interquartile range, whiskers extend to the range of the data.
42
BIBLIOGRAPHY
1. Rawal N, Hylander J, Nydahl PA, Olofsson I, Gupta A. Survey of postoperative analgesia following ambulatory surgery. Acta Anaesthesiol Scand 1997;41:1017-22. 2. van Geffen GJ, Moayeri N, Bruhn Jr, Scheffer GJ, Chan VW, Groen GJ. Correlation Between Ultrasound Imaging, Cross-Sectional Anatomy, and Histology of the Brachial Plexus: A Review. Regional Anesthesia and Pain Medicine 2009;34:490-7. 3. Borgeat A, Ekatodramis G, Kalberer F, Benz C. Acute and nonacute complications associated with interscalene block and shoulder surgery: a prospective study. Anesthesiology 2001;95:875-80. 4. Hadzic A, Williams BA, Karaca PE, et al. For outpatient rotator cuff surgery, nerve block anesthesia provides superior same-day recovery over general anesthesia. Anesthesiology 2005;102:1001-7. 5. Singelyn FJ, Seguy S, Gouverneur JM. Interscalene brachial plexus analgesia after open shoulder surgery: continuous versus patient-controlled infusion. Anesth Analg 1999;89:1216-20. 6. Borgeat A, Tewes E, Biasca N, Gerber C. Patient-controlled interscalene analgesia with ropivacaine after major shoulder surgery: PCIA vs PCA. British Journal of Anaesthesia 1998;81:603-5. 7. Tuominen M, Haasio J, Hekali R, Rosenberg PH. Continuous interscalene brachial plexus block: clinical efficacy, technical problems and bupivacaine plasma concentrations. Acta Anaesthesiol Scand 1989;33:84-8. 8. Klein SM, Steele SM, Nielsen KC, et al. The difficulties of ambulatory interscalene and intra-articular infusions for rotator cuff surgery: a preliminary report. Canadian Journal of Anaesthesia 2003;50:265-9. 9. Casati A, Fanelli G, Albertin A, et al. Interscalene brachial plexus anesthesia with either 0.5% ropivacaine or 0.5% bupivacaine. Minerva Anestesiol 2000;66:39-44. 10. Klein SM, Greengrass RA, Steele SM, et al. A comparison of 0.5% bupivacaine, 0.5% ropivacaine, and 0.75% ropivacaine for interscalene brachial plexus block. Anesth Analg 1998;87:1316-9. 11. Andan T, Elif AA, Ayse K, Gulnaz A. Clonidine as an adjuvant for lidocaine in axillary brachial plexus block in patients with chronic renal failure. Acta Anaesthesiol Scand 2005;49:563-8. 12. Erlacher W, Schuschnig CS, Koinig H, et al. Clonidine as adjuvant for mepivacaine, ropivacaine and bupivacaine in axillary, perivascular brachial plexus block. Canadian Journal of Anaesthesia 2001;48:522-5. 13. Duma A, Urbanek B, Sitzwohl C, Zimpfer M, Kapral S. Clonidine as an adjuvant to local anesthetic axillary brachial plexus block: a randomized, controlled study. British Journal of Anaesthesia 2005;94:112-6. 14. Nishikawa K, Kanaya N, Nakayama M, Igarashi M, Tsunoda K, Namiki A. Fentanyl improves analgesia but prolongs the onset of axillary brachial plexus block by peripheral mechanism. Anesth Analg 2000;91:384-7. 15. Karakaya D, Buyukgoz F, Baris S, Guldogus F, Tur A. Addition of fentanyl to bupivacaine prolongs anesthesia and analgesia in axillary brachial plexus block. Regional Anesthesia and Pain Medicine 2001;26:434-8.
43
16. Fanelli G, Casati A, Magistris L, et al. Fentanyl does not improve the nerve block characteristics of axillary brachial plexus anesthesia performed with ropivacaine. Acta Anaesthesiol Scand 2001;45:590-4. 17. Candido KD, Franco CD, Khan MA, Winnie AP, Raja DS. Buprenorphine added to the local anesthetic for brachial plexus block to provide postoperative analgesia in outpatients. Reg Anesth Pain Med 2001;26:352-6. 18. Candido KD, Winnie AP, Ghaleb AH, Fattouh MW, Franco CD. Buprenorphine added to the local anesthetic for axillary brachial plexus block prolongs postoperative analgesia. Reg Anesth Pain Med 2002;27:162-7. 19. Candido KD, Hennes J, Gonzalez S, et al. Buprenorphine Enhances and Prolongs the Postoperative Analgesic Effect of Bupivacaine in Patients Receiving Infragluteal Sciatic Nerve Block. Anesthesiology 2010;113:1419-26. 20. Gebhardt B. Pharmacology and clinical results with peridural and intrathecal administration of ketamine. Anaesthesist 1994;43 Suppl 2:S34-40. 21. Iida H, Dohi S, Tanahashi T, Watanabe Y, Takenaka M. Spinal conduction block by intrathecal ketamine in dogs. Anesth Analg 1997;85:106-10. 22. Noyan A. On effects of ketamine to axillary block in hand surgery. Journal of Reconstructive Microsurgery 2002;18:197. 23. Clerc S, Vuillermier H, Frascarolo P, Spahn DR, Gardaz J. Is the effect of inguinal field block with 0.5% bupivacaine on postoperative pain after hernia repair enhanced by addition of ketorolac or S(+) ketamine? Clinical Journal of Pain 2005;21:101-5. 24. Vranken JH, Troost D, de Haan P, et al. Severe toxic damage to the rabbit spinal cord after intrathecal administration of preservative-free S(+)-ketamine. Anesthesiology 2006;105:813-8. 25. Sauerland S, Nagelschmidt M, Mallmann P, Neugebauer EA. Risks and benefits of preoperative high dose methylprednisolone in surgical patients: a systematic review. Drug Saf 2000;23:449-61. 26. Schulze S, Andersen J, Overgaard H, et al. Effect of prednisolone on the systemic response and would healing after colonic surgery. Archives of Surgery 1997;132:129-35. 27. Movafegh A, Razazian M, Hajimaohamadi F, Meysamie A. Dexamethasone added to lidocaine prolongs axillary brachial plexus blockade. Anesth Analg 2006;102:263-7. 28. Stan T, Goodman EJ, Bravo-Fernandez C, Holbrook CR. Adding methylprednisolone to local anesthetic increases the duration of axillary block. Reg Anesth Pain Med 2004;29:380-1. 29. Shrestha BR, Maharjan SK, Tabedar S. Supraclavicular brachial plexus block with and without dexamethasone - a comparative study. Kathmandu Univ 2003;1:158-60. 30. Khafagy H, Refaat A, El-sabae H, Youssif M. Efficacy of epidural dexamethasone versus fentanyl on postoperative analgesia. Journal of Anesthesia 2010;24:531-6. 31. Parrington SJ, O'Donnell D, Chan VWS, et al. Dexamethasone Added to Mepivacaine Prolongs the Duration of Analgesia After Supraclavicular Brachial Plexus Blockade. Regional Anesthesia and Pain Medicine 2010;35:422-6. 32. Vieira PA, 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. 33. 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. Receptors Channels 1993;1:287-93.
44
34. Kopacz DJ, Lacouture PG, Wu D, Nandy P, Swanton R, Landau C. The dose response and effects of dexamethasone on bupivacaine microcapsules for intercostal blockade (T9 to T11) in healthy volunteers. Anesth Analg 2003;96:576-82. 35. Ruetsch YA, Boni T, Borgeat A. From cocaine to ropivacaine: the history of local anesthetic drugs. Curr Top Med Chem 2001;1:175-82. 36. Casati A, Putzu M. Bupivacaine, levobupivacaine and ropivacaine: are they clinically different? Best Pract Res Clin Anaesthesiol 2005;19:247-68. 37. Kee WDN, Ng FF, Khaw KS, Lee A, Gin T. Determination and Comparison of Graded Dose-Response Curves for Epidural Bupivacaine and Ropivacaine for Analgesia in Laboring Nulliparous Women. Anesthesiology;113:445-53. 38. Winnie AP. Interscalene brachial plexus block. Anesth Analg 1970;49:455-66. 39. Wiener DN, Speer KP. The deltoid sign. Anesth Analg 1994;79:192. 40. American Pain Society. Principles Of Analgesic Use In The Treatment Of Acute And Cancer Pain. Fifth ed. Glenview, IL: American Pain Society; 2003. 41. Hwang IK, Shih WJ, De Cani JS. Group sequential designs using a family of type I error probability spending functions. Stat Med 1990;9:1439-45. 42. Neal JM, Rathmell JP, Rowlingson JC. Publishing Studies That Involve "Off-label" Use of Drugs: Formalizing Regional Anesthesia and Pain Medicine's Policy. Regional Anesthesia and Pain Medicine 2009;34:391-2 10.1097/AAP.0b013e3181b87066. 43. Johansson A, Dahlin L, Kerns JM. Long-term local corticosteroid application does not influence nerve transmission or structure. Acta Anaesthesiol Scand 1995;39:364-9. 44. 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. 45. Benzon HT, Gissen AJ, Strichartz GR, Avram MJ, Covino BG. The effect of polyethylene glycol on mammalian nerve impulses. Anesth Analg 1987;66:553-9. 46. Price C, Arden N, Coglan L, Rogers P. Cost-effectiveness and safety of epidural steroids in the management of sciatica. Health Technology Assessment (Winchester, England);9:1-58. 47. Williams BA, Neumann KJ, Goel SK, Wu C. Postoperative pain and other acute pain syndromes. In: Benzon HT, Rathmell JP, Wu CL, Turk DC, Argoff CE, eds. Raj's Practical Management of Pain. 4 ed. Philadelphia: Mosby Elsevier; 2008. 48. Racz GB, Noe CL. Pelvic spinal neuraxial procedures. In: Raj P, Lou L, Serdar E, et al., eds. Interventional Pain Management. 2 ed. Philadelphia: Saunders; 2008. 49. Apfel CC, Korttila K, Abdalla M, et al. A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl J Med 2004;350:2441-51. 50. Pasternak JJ, McGregor DG, Lanier WL. Effect of single-dose dexamethasone on blood glucose concentration in patients undergoing craniotomy. J Neurosurg Anesthesiol 2004;16:122-5. 51. Bisgaard T, Klarskov B, Kehlet H, Rosenberg J. Preoperative dexamethasone improves surgical outcome after laparoscopic cholecystectomy: a randomized double-blind placebo-controlled trial. Ann Surg 2003;238:651-60. 52. Nagelschmidt M, Fu ZX, Saad S, Dimmeler S, Neugebauer E. Preoperative high dose methylprednisolone improves patients outcome after abdominal surgery. Eur J Surg 1999;165:971-8. 53. Aasboe V, Raeder JC, Groegaard B. Betamethasone reduces postoperative pain and nausea after ambulatory surgery. Anesth Analg 1998;87:319-23.
45
54. Kardash KJ, Sarrazin F, Tessler MJ, Velly AM. Single-Dose Dexamethasone Reduces Dynamic Pain After Total Hip Arthroplasty. Anesth Analg 2008;106:1253-7.
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