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Original article
Addition of dexamethasone to local infiltration analgesia in elective total hip arthroplasty: a double-blind, randomized control trial
  1. Kariem El-Boghdadly1,2,
  2. Anthony James Short3,
  3. Rajiv Gandhi4 and
  4. Vincent W S Chan5
  1. 1Department of Anaesthesia, Guy’s and St Thomas’ NHS Foundation Trust, London, UK
  2. 2King’s College London, London, UK
  3. 3Department of Anaesthetics, Wrightington, Wigan and Leigh NHS Foundation Trust, Wigan, UK
  4. 4Division of Orthopedic Surgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada
  5. 5Anesthesia, University of Toronto, Toronto, Ontario, Canada
  1. Correspondence to Dr Kariem El-Boghdadly, Department of Anaesthesia, Guy’s and St Thomas’ NHS Foundation Trust, London SE1 7EH, UK; elboghdadly{at}gmail.com

Abstract

Background and objectives Pain following total hip arthroplasty is significant, and effective analgesia is associated with an improvement in functional outcomes. Dexamethasone may facilitate the action of local anesthesia, but its role as an additive to a local infiltration analgesia (LIA) mixture in hip arthroplasty settings has not been investigated. We hypothesized that the addition of dexamethasone to local anesthetic infiltration improves analgesic outcomes following total hip arthroplasty.

Methods We performed a double-blind, randomized control trial of 170 patients undergoing total hip arthroplasty. Patients were randomized to receive LIA mixed with either 2 mL of saline 0.9% or 2 mL of dexamethasone 4 mg/mL. The primary outcome was 24 hours oral morphine consumption. Secondary outcomes included short-term and long-term analgesic and functional outcomes and adverse events.

Results 85 patients were included in each arm. 24 hours morphine consumption was similar between saline and dexamethasone groups, with a median (IQR (range)) of 75 (45–105 (0–240)) and 62.5 (37.5–102.5 (0–210)) mg, respectively (p=0.145). However, patients receiving dexamethasone had significantly reduced opioid consumption for their total in-hospital stay, but not at any other time points examined. Functional outcomes were similar between groups. The incidence of postoperative nausea and vomiting was reduced in patients receiving dexamethasone.

Conclusions The addition of 8 mg dexamethasone to LIA did not reduce 24 hours morphine consumption but was associated with limited improvement in short-term analgesic outcomes and a reduction in postoperative nausea and vomiting. Dexamethasone had no effect on functional outcomes or long-term analgesia.

Trial registration number NCT02760043

  • Hip surgery
  • dexamethasone
  • regional anesthesia
  • orthopedics
  • local anaesthesia

https://doi.org/10.1136/rapm-2019-100873

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    Background

    Pain following total hip arthroplasty is significant,1 and effective analgesia in the immediate postoperative period has been shown to improve ambulation and surgical outcomes, and reduce the progression to chronic pain.2 3 Moreover, the opioid epidemic means that alternative strategies to mitigate the use of opioids must be considered.4 Systemic analgesia alone is associated with adverse events, reduced analgesic efficacy, and lower patient satisfaction compared with regional anesthesia techniques.5–7 Moreover, the use of regional anesthesia is associated with a reduction in the length of hospital stay and postoperative cognitive dysfunction.7 Therefore, the use of regional anesthesia techniques within a multimodal analgesic strategy in patients undergoing elective total hip arthroplasty is advantageous.

    Local infiltration analgesia (LIA) is a multimodal technique involving infiltration of large volumes of low-concentration local anesthesia in conjunction with various additives, including non-steroidal anti-inflammatory drugs, opioids, and epinephrine.8–10 It is simple to perform and is associated with a low risk of motor weakness.11 When compared with intrathecal morphine, epidural analgesia, or peripheral nerve blocks, LIA has comparable analgesic efficacy.12–15 There is also direct evidence that LIA has benefits on functional recovery after hip arthroplasty.16 However, the limited duration of action of LIA has been regarded as a weakness of this technique,17 and whether the addition of adjuncts to LIA mixtures can extend its duration of activity is currently unclear.18

    One particular drug that is underevaluated in this setting is dexamethasone. Clinical studies demonstrating facilitatory effects of perineural and systemic dexamethasone suggest that this long-acting glucocorticoid may prolong the duration and clinical effectiveness of LIA.19 Its mechanism of action is presumably mediated through a reduction in the production of peripheral inflammatory mediators,20 which may have benefits on pain and functional recovery.12 Periarticular steroids have been shown to reduce hospital length of stay,21 improve short-term pain scores,20 improve functional outcomes,22 and reduce inflammatory markers23 following total joint arthroplasty, most commonly knee arthroplasty, without any increased risks of infection.24 25 However, there have been no randomized controlled trials assessing the effects of dexamethasone as an additive to an LIA mixture for total hip arthroplasty.

    We, therefore, sought to determine the effects of adding dexamethasone to an LIA mixture on outcomes after primary, elective, unilateral total hip arthroplasty. We hypothesized that the addition of dexamethasone would improve short-term analgesic outcomes.

    Methods

    This prospective, randomized, double-blind, placebo-controlled, superiority clinical trial was registered on www.clinicaltrials.gov prospectively. The trial was conducted at Toronto Western Hospital between April 2016 and June 2018. The conduct of this study followed the Declaration of Helsinki principles and the reporting of this study adhered to the Consolidated Standards of Reporting Trials guidelines for randomized controlled trials.26 27

    Participants

    We included male and female, American Society of Anesthesiologists physical status 1–4 patients, aged 18–85 years, weighing 50–100 kg, with a body mass index of 18–40 kg/m2, and undergoing elective primary, unilateral hip arthroplasty under spinal anesthesia. Exclusion criteria were revision or bilateral arthroplasty procedures, contraindications to spinal anesthesia, intraoperative general anesthesia, allergy to any of the study medications, chronic pain state or opioid dependence unrelated to hip pathology (defined as ongoing requirement of opioids for analgesic management of any ongoing pain state that is unrelated to hip pathology for longer than 12 weeks), and significant peripheral neuropathy. Most patients were identified and screened by a research assistant at the time of their pre-admission visit, provided the details of the clinical trial procedures, and given time to consider enrollment. Some patients were consented on the day of surgery, but identical consent procedures were observed.

    Randomization and blinding

    After written informed consent was taken, patients were randomly allocated to one of the two groups in a 1:1 ratio using a computer-generated list of random numbers with a block randomization technique (www.randomization.com) by a research assistant. A unique randomization code was used with no restrictions to either of the two study groups: LIA with saline or LIA with dexamethasone. The results of the randomization were maintained in opaque envelopes and stored with the research coordinator. These sealed, opaque envelopes were given to the operating room nurse who then prepared the LIA mixture either with saline or dexamethasone according to the randomization code. This operating room nurse had no further participation in any aspect of the study. The final LIA mixtures appeared identical. The patient, anesthesiologist, surgeon, physiotherapists, acute pain nurses, and outcome assessors were unaware of study group allocation.

    Perioperative management

    All patients received 650–1000 mg acetaminophen orally, adjusted to weight, and 100–200 mg celecoxib before surgery unless contraindicated. All patients received spinal anesthesia in a designated regional anesthesia room. After placement of non-invasive blood pressure, ECG, and pulse oximetry monitors, as well as a facemask with supplemental oxygen and intravenous access, patients were then positioned in the sitting position, and their backs were prepared with 2% chlorhexidine gluconate in 70% isopropyl alcohol for spinal anesthesia. Patients were then given intravenous midazolam 1–2 mg and intravenous fentanyl 25–50 µg, as needed. Spinal anesthesia was performed under sterile, aseptic conditions, with a 25-gauge 90 or 120 mm Whitacre needle introduced at the L2–3, L3–4, or L4–5 intervertebral levels to enter the intrathecal space. All patients received 3 mL of 0.5% preservative-free isobaric plain bupivacaine with or without intrathecal morphine 100 µg. Patients were then positioned in the lateral decubitus position with the surgical side uppermost, and loss of pinprick sensation in the T10–L5 dermatomes was confirmed prior to transfer to the operating room for surgery.

    In the operating room, patients underwent total hip arthroplasty in the lateral decubitus position and received oxygen via facemask to maintain oxygen saturation of more than 92%, unless otherwise indicated. Conscious sedation was titrated to patient comfort in the form of either a propofol infusion (25–75 µg/kg/min) or intermittent boluses of intravenous midazolam in 1 mg increments, and intravenous fentanyl in 1–2 µg/kg increments, as required. No long-acting opioid was administered intraoperatively. No patients received intravenous dexamethasone at any time during the perioperative period. All other perioperative procedures adhered to standard institutional practices. All total hip arthroplasty procedures were performed by fellowship-trained, high-volume surgeons. All patients underwent a standard lateral approach total hip arthroplasty with uncemented implants, with division of the abductor medius and minimus to access the joint. All tendon divisions were repaired before wound closure.

    Once the prosthesis was implanted, LIA was performed by the surgeon under direct vision with 300 mg of ropivacaine (150 mL of 0.2% ropivacaine), 30 mg of ketorolac, and 0.6 mg of epinephrine. The saline group received this LIA mixture with 2 mL 0.9% saline added, while the dexamethasone group had the same solution but with the addition of 2 mL dexamethasone sodium phosphate (Omega, Montreal, Quebec, Canada) 4 mg/mL (8 mg). Equal volumes were injected to the gluteus minimus, medius, vastus lateralis, tensor fascia, and subcutaneous tissue to ensure complete coverage of the joint structures.

    Postoperative management

    After completion of the surgery, patients were transferred to the postanesthetic care unit (PACU), where they had access to multimodal analgesia if required, administered by a PACU nurse blinded to the treatment allocation. This included fentanyl in 25 µg increments every 5 min up to 200 µg or hydromorphone in 0.2 mg increments up to 2 mg. Nausea and vomiting were treated with intravenous dimenhydrinate 25 mg and/or intravenous ondansetron 4 mg, as required. Once patients achieved an Aldrete score of 9,28 they were considered safe for discharge to the ward.

    Postoperatively, all patients were prescribed regular oral acetaminophen 650–1000 mg 6 hourly and oral celecoxib 100–200 mg two times per day, unless contraindicated. Immediate-release oral oxycodone 5–10 mg or hydromorphone 1–2 mg every 2 hours was prescribed as required. In the event of inadequate analgesia with oral analgesia alone, defined as the failure to achieve a numerical rating scale (NRS) of <5 with oral analgesia alone, intravenous patient-controlled analgesia (PCA) with hydromorphone or morphine was commenced as a rescue modality. Patients were followed-up two times per day by the Acute Pain Service team who had the liberty to modify the analgesic regimen as required.

    Outcome measures

    The primary outcome was the cumulative opioid consumption measured as oral morphine equivalents (mg) at 24 hours following PACU arrival. All opioids were converted to oral morphine equivalents using standardized conversion ratios.29

    Secondary analgesic outcomes included pain scores as assessed by an 11-point NRS, where 0 is “no pain” and 10 is “the worst pain imaginable,” both at rest and during active movement preoperatively and in PACU and at the following time points: at rest between 08:00 and 10:00 and during physiotherapy on postoperative day (POD) 1, 2, and 3, if still in hospital. The proportion of patients requiring rescue intravenous PCA at any time in the postoperative period was also collected, as well as the time to first analgesic request and the incidence of opioid-related side effects, including nausea and vomiting requiring treatment with antiemetic medications, pruritus requiring treatment with antihistamines, or oversedation requiring treatment with naloxone. The proportion of patients experiencing pain at 3 months was determined using the Douleur Neuropathique 4 (DN4) questionnaire.30

    Secondary functional outcomes included the timed up and go (TUG) test31 and active range of motion, defined as hip flexion from neutral (0°) to maximum flexion, measured preoperatively and during daily physiotherapy sessions. TUG was only measured on POD 2 and, if still in hospital, POD 3. Range of motion was only measured on POD 1 and the distance walked was measured on PODs 1 and 2. Long-term self-reported functional outcomes were measured at baseline and 3 months postoperatively, including the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)32 and the lower extremity functional scale (LEFS).33

    Other outcomes sought included all in-hospital complications (including urinary retention, hemodynamic disturbance, falls, cardiac, neurological, joint complications, or venous thromboembolism), discharge destination, and hospital length of stay, defined as the number of days from admission to discharge, inclusive. The National Surgical Quality Improvement Program database was also queried for evidence of any organ/space infection (ie, infection that involves any part of the anatomy other than the incision) or superficial surgical site infection within 30 days of surgery. All outcomes were collected by members of the research team that were blinded to allocation of intervention by analyzing hospital records.

    Sample size

    We selected cumulative 24 hours oral morphine consumption equivalent as our primary outcome. Based on the data published by Murphy et al, who reported 24 hours oral morphine consumption in patients who had primary total hip arthroplasty with LIA and no dexamethasone, the mean (SD) dose of cumulative oral morphine equivalent consumption was 85.5 (56.7) mg.34 To demonstrate that the addition of dexamethasone reduces analgesic 24 hours opioid consumption by 30%,35 77 patients per group were required to detect a statistically significant difference with an α of 0.05 and 80% power. Allowing for approximately a 10% incomplete follow-up or patient dropout, we aimed to recruit 85 patients per group, with a total sample size of 170 patients.

    Statistical analysis

    An intention-to-treat data analysis plan was designed. Subjects were included if they were randomized and there were data available for the primary outcome. Data were analyzed using SPSS V.23.0 for Mac, and normality was tested using the Shapiro-Wilk test. Parametric data were reported as mean (SD), non-parametric data as median (IQR (range)), and discreet variables as percentages. χ2 analysis was used for intergroup differences between categorical variables. For parametric data, the Student’s unpaired t-test was used to demonstrate differences between groups, and the Mann-Whitney U test was applied to non-parametric continuous variables. Bonferroni correction was used for multiple comparisons in all analyses, and p<0.05 was considered statistically significant.

    Results

    A total of 417 patients were screened between 13 April 2016 and 25 June 2018, of which 170 were enrolled and underwent randomization. A total of 85 patients were recruited to each group with no dropouts, incomplete data, or loss to follow-up for the primary outcome or in-hospital secondary outcomes (figure 1). However, 3-month follow-up for 30 patients in the saline group and 25 patients in the dexamethasone group was incomplete due to failure to contact patients. Subjects in both groups had similar demographics (table 1). There was no difference in the number of patients receiving intrathecal morphine (≤0.1 mg) between the groups (27.0% vs 16.5%, p=0.094).

    View this table:
    Table 1

    Baseline demographics of study subjects

    Figure 1
    Figure 1

    CONSORT flow diagram of subject enrollment, allocation, follow-up, and statistical analysis. CONSORT, Consolidated Standards of Reporting Trials.

    There was no significant difference in the primary outcome of cumulative 24 hours oral morphine equivalent consumption between saline and dexamethasone groups, with a median (IQR (range)) of 75 (45–105 (0–240)) and 62.5 (37.5–102.5 (0–210)) mg, respectively (p=0.145). For secondary analgesic outcomes, there was a statistically significant but clinically uncertain reduction in oral morphine equivalent consumption in the dexamethasone group compared with the saline group for total in-hospital stay (p=0.025), but not at any other time points examined (table 2). There was no significant difference in the time to first analgesic request (186 (143–239.5 (10–688)) min for the saline group vs 165 (109–259 (0–1251)) min for the dexamethasone group, p=0.336). There was also no difference in the incidence of rescue PCA use between the two groups (saline 27.0% vs dexamethasone 17.6%, p=0.141). Mean (SD) NRS pain scores at rest were statistically significantly different between the two groups at PODs 1 (saline 3.76 (1.78) vs dexamethasone 2.79 (1.69), p<0.001) and 2 (saline 2.85 (1.53) vs dexamethasone 2.33 (1.41), p=0.03). Mean (SD) NRS pain scores with activity were also significantly lower in the dexamethasone group on POD 1 (saline 6.39 (1.92) vs dexamethasone 5.31 (2.06), p=0.001) and approached significance on POD 2 (saline 5.03 (1.73) vs dexamethasone 4.47 (1.80), p=0.05). There were no other differences in pain scores at any other time points (figure 2).

    View this table:
    Table 2

    Oral morphine equivalent consumption (mg) at different time points

    Figure 2
    Figure 2

    Passive (A) and active (B) mean (SD) numerical rating scale pain scores at rest (A) and with activity (B). * represents statistically significant difference after correction for multiple outcome testing. PACU, postanesthetic care unit; POD, postoperative day.

    On subgroup analysis, the use of intrathecal morphine did not affect postoperative pain scores or opioid consumption. However, oral morphine equivalent consumption at 48–72 hours was lower in patients who did not receive intrathecal morphine than for patients who did in both saline (p<0.001) and dexamethasone (p=0.031) groups.

    There were no differences in TUG tests, range of motion, and distance walked at any of the time points measured (table 3). There was no difference in the reduction of WOMAC scores 3 months after surgery from baseline (p=0.475) or the LEFS scores (p=0.774) between the two groups. In addition, no patients in either group had chronic pain according to the DN4 questionnaire.

    View this table:
    Table 3

    In-hospital functional outcomes

    Patients in the saline group had a higher incidence of postoperative nausea on PODs 0 and 1, and vomiting on POD 0. Otherwise, there was no significant difference in the incidence of any other adverse events, including joint complications or surgical site infection (table 4).

    View this table:
    Table 4

    Complications in each group

    Discussion

    This is one of the largest clinical trials examining the analgesic efficacy of dexamethasone with LIA and the only prospective trial in the hip arthroplasty population. We demonstrated no difference in our primary outcome of 24 hours oral morphine consumption, but a statistically significant, although probably clinically insignificant, impact on other analgesic outcomes of the addition of dexamethasone 8 mg to an LIA mixture in patients having primary, unilateral, total hip arthroplasty. Our results are consistent with the baseline opioid utilization that we have used to power our study.34 Locally administered dexamethasone was also associated with a reduction in postoperative nausea and vomiting, as the saline group did not receive intravenous dexamethasone. However, the addition of dexamethasone to LIA had no effect on short-term or long-term functional outcomes.

    There are several clinical trials reporting the short-term analgesic benefits of the addition of corticosteroids to an LIA mixture in the knee arthroplasty population. Despite high heterogeneity in the design and quality of these randomized trials, the analgesic efficacy of steroids appears high in these settings.36 37 Benefits on length of stay, inflammatory markers, and functional outcomes have been demonstrated with a range of steroids other than dexamethasone, including methylprednisolone, betamethasone, and triamcinolone.38 However, there is little published on the analgesic or functional efficacy of dexamethasone added to LIA in the hip arthroplasty population. Our data, therefore, provide a valuable addition to the literature and may go some way to further our understanding of the role of dexamethasone.

    Dexamethasone has been shown to facilitate peripheral nerve blockade in a range of nerve block techniques and operative settings. The data, thus, far suggest that dexamethasone is effective regardless of the perineural or systemic (intravenous) route of administration.19 39–41 While the precise mechanism is unclear, recent volunteer studies suggest that the effect of dexamethasone may be related to the systemic anti-inflammatory effects of dexamethasone, rather than a direct effect on peripheral nerves.42 Indeed, systemically administered dexamethasone without the use of local anesthesia has been shown to have analgesic properties, further supporting a systemic mechanism.43

    Although we demonstrated no differences in our primary outcome, 24 hours oral morphine equivalent consumption, we found a statistically significant difference in analgesic consumption overall. Similarly, there was a difference in NRS pain scores on the first POD of approximately 1 point, which might be clinically important,44 and to a lesser extent on POD 2, which are in keeping with the duration of action of dexamethasone.45 In addition, the reduced incidence of postoperative nausea and vomiting in the dexamethasone group suggests a systemic mechanism of action of LIA dexamethasone might be possible. One possibility might be that a higher dose of dexamethasone could have led to more pronounced effects on analgesic and functional outcomes. Indeed, one may postulate that systemically administered dexamethasone might also demonstrate equivalent efficacy and safety to that added to LIA.37

    This study has some limitations. Several patients received intrathecal morphine, which may have influenced analgesic outcomes. However, there were no differences between both arms in the number of patients receiving intrathecal morphine and subgroup analyses demonstrate that the impact on results is inconsequential. Our LIA mixture included both epinephrine and ketorolac, which could mean that we are unable to exclude potential masking of the effect of dexamethasone by the other two adjuvants. However, this mixture is both institutional standard, as well as a commonly used mixture in studies of LIA, and we aimed to facilitate this mixture.14 In addition, the choice of postoperative opioids was not standardized. However, this was a pragmatic decision that was addressed by converting all opioid dosing to oral morphine equivalents, and therefore should have a limited impact on our results. Moreover, we were unable to attribute the dose of opioid administered via PCA, as this was combined in the total opioid consumption. However, we expect that this has little bearing on our results as the total opioid consumption is a more relevant metric. Another limitation is that some have suggested that primary hip arthroplasty is generally not perceived to represent a high postoperative pain load when compared with other large joint arthroplasties,46 which might make it more challenging to find a clinically important difference in analgesic outcomes with the addition of dexamethasone to LIA. However, contemporary data demonstrate that postoperative pain scores are similar in both hip and knee arthroplasty patients,47 and therefore, this criticism is of limited relevance, meaning this population remains an important avenue of investigation. An additional limitation was that we had selected an 8 mg dose of dexamethasone for addition. While dose-dependent effects of dexamethasone have been demonstrated in other settings, we do not know the optimal dose in an LIA mixture. We, therefore, selected a dose that was equipotent to previously reported studies and has been suggested to be safe in this setting.38 48 Finally, this was a single-center study, and therefore, the generalizability of the data must be tempered until further studies are conducted. Future clinical trials should examine the relationship between dose of dexamethasone or route of administration on analgesic effectiveness, which should include a direct comparison between systemic and LIA-administered dexamethasone. The addition of other adjuvants should also be explored.

    In conclusion, the addition of dexamethasone 8 mg to LIA was not associated with clinically important analgesic benefits in patients undergoing elective total hip arthroplasty but was associated with a reduction in postoperative nausea and vomiting and no deleterious effect on functional outcomes.

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    Footnotes

    • Twitter @elboghdadly, @tony_short

    • Contributors Study design: KE-B, AJS, RG, and VWSC. Study conduct: KE-B, RG, and VWSC. Data analysis: KE-B, AJS, and VWSC. Manuscript preparation: KE-B. Manuscript revision: KE-B, AJS, RG, and VWSC. Manuscript approval: KE-B, AJS, RG, and VWSC.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Ethics approval This trial was approved by the University Health Network Research and Ethics Board (15-9898-A).

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement Data are available on reasonable request.