Perineural and Systemic Dexamethasone and Ulnar Nerve Block Duration: A Randomized, Blinded, Placebo-controlled Trial in Healthy Volunteers

This was a randomized, blinded, placebo-controlled, paired, crossover trial in healthy volunteers. The trial was approved by the Regional Ethics Committee of the Zealand Region of Denmark (SJ-886; Copenhagen, Denmark) and the Danish Medicines Agency (EudraCT 2020-004242-10; Copenhagen, Denmark). The trial was registered with the Data Protection Agency of the Zealand Region of Denmark. We prospectively registered the trial at ClinicalTrials.gov on March 26, 2021 (NCT04817982, principal investigator: Mathias Maagaard). The Good Clinical Practice Unit at the Copenhagen University Hospital (Copenhagen, Denmark) monitored the conduct of the trial. We report this trial according to the Consolidated Standard of Reporting Trials statement extension for noninferiority trials.¹⁵ 

This trial was conducted at the Zealand University Hospital (Køge, Denmark). We recruited participants using advertisements on social media and in a local medical school journal. Participants were enrolled between April 7, 2021, and May 15, 2021. Inclusion criteria were age 18 yr or older, body mass index between 18 and 30 kg/m², and American Society of Anesthesiologists Physical Status of 1 to 2. Female participants were required to use safe contraceptives and present a negative urine human chorionic gonadotropin test. Exclusion criteria were inability to speak or read Danish, allergy to study medication, age older than 65 yr, cardiovascular disease, history of alcohol or substance abuse, use of corticosteroids within 14 days, intake of prescription analgesics within 4 weeks, intake of over-the-counter analgesics within 48 h, neuromuscular disease or wounds preventing adequate testing or block performance, and diabetes mellitus. Written informed consent was obtained before inclusion in the trial. The participants attended two trials days at least 14 days apart.

The participants received bilateral ultrasound-guided ulnar nerve blocks using a linear 12-l ultrasound probe. Experienced anesthesiologists performed the ulnar nerve blocks. The ulnar nerve was identified medially on the proximal forearm. A 22-gauge, 50 mm SonoBlock Facet Tip needle (Pajunk Medical Systems, USA) was inserted in-plane through the flexor carpi ulnaris muscle. The study medication was slowly injected around the ulnar nerve, ensuring a circumferential spread of the study medication. All participants first received an ulnar nerve block in their right arm, followed immediately by an ulnar nerve block in their left arm.

All participants received bilateral ulnar nerve blocks with 3 ml bupivacaine 5 mg/ml. On one trial day, 1 ml dexamethasone 4 mg/ml + 1 ml isotonic saline was added to the bupivacaine in one of the participants’ arms (perineural condition), and 2 ml isotonic saline was added to bupivacaine in the other arm (systemic condition). On the other trial day, 2 ml isotonic saline was added to bupivacaine in one of the participants’ arms (placebo condition), and 2 ml lidocaine 20 mg/ml was added to the other arm (lidocaine condition). The lidocaine condition was included to preserve blinding and investigate the effects of adding lidocaine to bupivacaine. The participants were randomly assigned by a simple computer-generated random allocation sequence generated by an independent statistician not otherwise involved in the trial. The allocation was concealed in sequentially numbered opaque envelopes. The investigators assigned the participants consecutively on inclusion. The participants randomly received the trial medication combinations on either trial day 1 or 2 and randomly received the trial medication perineurally around their right or left ulnar nerve. An unblinded nurse, who was not otherwise involved in the trial, prepared the study medication according to the allocation in the envelopes. The nurse did not open the envelopes until the participants were allocated. The study medication was identical in appearance and was prepared in identical 5-ml syringes and marked with participant identification and either “right arm” or “left arm.” The participants, the anesthesiologists performing the blocks, and the investigators performing the outcome assessments were all blinded to treatment allocation.

We assessed the duration of the sensory nerve block using three sensory tests and the duration of the motor block using one test. We assessed the onset of the sensory nerve block using one test. We measured the onset of the motor block as part of our assessment of block success using one test and post hoc decided to also report on this outcome. The sensory tests modalities were tested in the hypothenar area. The tests were repeated every minute for the assessment of block onset, and every 30 min for the assessment of the duration of the block.

The onset of the sensory block was defined as the time from block performance until an alcohol swab no longer felt cold. The duration of the sensory block measured by temperature discrimination was defined as the time from block performance until an alcohol swab felt cold again.

The duration of the sensory nerve block measured by mechanical discrimination was defined as the time from block performance until a needle was perceived as sharp again.

This outcome was included as an attempt to mimic the duration of analgesia. A computer-controlled thermode (2.5 cm², Thermotest, Somedic A/B, Hörby, Sweden) was heated to 45°C for 30 s to induce clinical pain. The duration of the sensory block measured by pain during tonic heat stimulation was defined as the time from block performance until the tonic heat stimulation induced a painful response on the Numerical Rating Scale (greater than 0).

The motor block was tested by immobilizing the hand except for the fifth finger, thereby only allowing abduction of the fifth finger. The motor block was then assessed on the Modified Bromage Scale where the onset of the motor block was defined as a Bromage of “0,” and the duration of the motor block was defined as the time from block performance until Bromage reached “4” again or the participant indicated a feeling of normal strength in their fifth finger.¹⁶ 

1. Duration of sensory nerve block measured by temperature discrimination

1. Duration of sensory block measured by mechanical discrimination

2. Duration of sensory block measured by pain during tonic heat stimulation

3. Duration of motor block measured by fifth finger abduction

4. Onset of sensory block measured by temperature discrimination

5. Onset of motor block measured by fifth finger abduction (post hoc added variable)

We aimed to test the joint hypotheses that both perineural dexamethasone and the subsequent systemic effects of dexamethasone would increase the duration of peripheral nerve blocks with bupivacaine and that systemic dexamethasone would be noninferior to perineural dexamethasone. We predefined a 33% difference in block duration to be important for the perineural and systemic dexamethasone conditions when compared with the placebo condition. A 33% increase in block duration has previously been used as a minimally important difference.^14,17  We predefined a noninferiority margin of 25% between perineural and systemic dexamethasone. A 25% noninferiority margin has also been used previously.^14,17 

We assumed a mean duration of 570.0 ± 114 min with the placebo condition based on another trial in healthy volunteers using a median nerve block.¹⁸  To estimate the expected block duration with the perineural condition and the systemic condition, we used the percentage increase in block duration by perineural and intravenous (systemic) dexamethasone from a Cochrane review.⁷  In the Cochrane review, placebo had a block duration of 10.2 h, and block duration was increased by a mean difference of 6.7 h with perineural dexamethasone (65.7% increase) in the placebo versus perineural dexamethasone comparison. In the comparison of placebo versus systemic dexamethasone, placebo had a block duration of 16.1 h, and the block duration was increased by a mean difference of 6.2 h with systemic dexamethasone (38.5%). For the perineural condition, we calculated the SD as an unweighted mean SD from the Cochrane review.⁷  For the systemic condition, we used the SD from the intravenous dexamethasone group in a trial in healthy volunteers.¹⁸  Subsequently, we expected a block duration of 944.5 (570 × 1.657) ± 273 min with the perineural condition and 789.5 (570 × 1.385) ± 222 min with the systemic condition. The assumed durations correspond to a standardized mean difference (Cohen’s d) between perineural dexamethasone and placebo of d = 1.8, between systemic dexamethasone and placebo of d = 1.2, and between perineural and systemic dexamethasone of d = 0.6. We assumed a correlation between perineural and systemic dexamethasone of 0.5 and a correlation between perineural/systemic dexamethasone and placebo of 0.1 based on correlations from a previous study using the same setup.¹⁴  A biostatistician determined that a sample size of 12 participants based on a significance level of 5% and simulation of 10,000 sample populations from independent multivariate Gaussian distributions (with multiple testing for the superiority of perineural dexamethasone vs. placebo, and systemic dexamethasone versus placebo, and noninferiority of perineural dexamethasone vs. systemic dexamethasone) would result in a minimum power of 83% for all comparisons. To account for the uncertainty of the underlying distribution, we chose to include 16 participants.

We assessed the outcome data for normality using boxplots and quantile-quantile plots. We presented summary statistics as mean with SD. We calculated mean differences, 95% CIs, and P values of the difference between the conditions using a paired t test. We tested a joint hypothesis that both perineural and systemic dexamethasone would increase sensory block duration as measured by temperature discrimination and that systemic dexamethasone would be noninferior to perineural dexamethasone. As the superiority of both perineural and systemic dexamethasone compared with placebo was mandatory for the noninferiority comparison, the three-way comparison could be regarded as a multiple one-dimensional test or hierarchical test. Furthermore, the superiority tests can be regarded as a conjunction test. Therefore, we did not adjust the threshold for statistical significance to account for multiplicity when assessing the primary outcome and the joint hypothesis. Furthermore, the secondary outcomes were planned to support the primary outcome. Thus, we used a P value of 0.05 as the threshold for statistical significance.

We planned to only assess for noninferiority of systemic dexamethasone versus perineural dexamethasone if the block durations with both the perineural condition and systemic dexamethasone condition were prolonged by more than 33% when compared with the placebo condition. We visually reported the percentage difference for each participant for the comparisons of perineural versus placebo, systemic versus placebo, lidocaine versus placebo, and perineural versus systemic. We post hoc decided to also analyze the onset of the motor block using fifth finger abduction. We post hoc also decided to analyze the primary outcome using a linear mixed-effects model accounting for the within-day clustering of block durations by participant. All statistical analyses were performed using RStudio 4.1.2.¹⁹ 

We screened 18 people for inclusion. One refused to participate, and one received concomitant glucocorticoid treatment. Thus, 16 healthy volunteers were included (fig. 1). We included nine female and seven male participants. They had a mean height of 178 cm, a mean weight of 78 kg, and a mean body mass index of 24 kg/m². All participants completed both trial days between April 7, 2021, and May 15, 2021. There were no failed or partial blocks. There were no missing data, and all participants were included in all analyses.

The duration of the sensory nerve block as measured by temperature discrimination was 706 ± 94 min with perineural dexamethasone, 677 ± 112 min with systemic dexamethasone, and 640 ± 121 min with placebo (fig. 2). Perineural dexamethasone resulted in greater duration when compared with placebo (mean difference 66 min; 95% CI, 23 to 108; P ≤0.001; see fig. 3 in Supplemental Digital Content 1, https://links.lww.com/ALN/D107, for individual patient differences). Systemic dexamethasone had a similar duration as placebo (mean difference 36 min; 95% CI, –30 to 103; P = 0.260; see fig. 4 in Supplemental Digital Content 2, https://links.lww.com/ALN/D108, for individual patient differences). According to our predefined statistical plan, we did not assess perineural and systemic dexamethasone for noninferiority because only perineural dexamethasone was superior to placebo. Adjunct lidocaine seemed to lessen the duration when compared with placebo (mean difference –189 min; 95% CI, –243 to –135; P < 0.001; see fig. 5 in Supplemental Digital Content 3, https://links.lww.com/ALN/D109, for individual patient differences). See figure 6 in Supplemental Digital Content 4 (https://links.lww.com/ALN/D110) for individual patient differences for the perineural versus systemic condition.

We post hoc performed a linear mixed-effects model with each condition (perineural, systemic, lidocaine, placebo) as fixed-effects and “day” clustered by “person” as random-effects to account for the complexity of the design. The reference was the placebo condition with an estimate of 640 min (95% CI, 582 to 699). The block duration was greater with the perineural condition with an estimate of 66 min (95% CI, 10 to 121), the duration was similar with the systemic condition with an estimate of 36 min (95% CI, –19 to 92), and the duration was lesser with the lidocaine condition with an estimate of –189 min (95% CI, –240 to –137).

In our study, a 33% increase by the systemic and perineural conditions when compared with placebo would correspond to a 211-min increase, while a 25% noninferiority margin by the systemic condition compared with the perineural condition would correspond to 177 min.

We found similar durations for both perineural dexamethasone (mean difference 8 min; 95% CI, –57 to 73; P = 0.791) and systemic dexamethasone (mean difference 20 min; 95% CI, –51 to 91; P = 0.559) when compared with placebo. However, adjunct lidocaine lessened the duration when compared with placebo (mean difference –230 min; 95% CI, –290 to –170; P < 0.001).

Sensory block duration was greater with both perineural dexamethasone (mean difference 72 min; 95% CI, 14 to 130; P = 0.018) and systemic dexamethasone (mean difference 82 min; 95% CI, 11 to 154; P = 0.026) when compared with placebo. However, adjunct lidocaine lessened the duration when compared with placebo (mean difference –180 min; 95% CI, –237 to –124; P < 0.001).

We found similar durations for both perineural dexamethasone (mean difference 10 min; 95% CI, –37 to 57; P = 0.654) and systemic dexamethasone (mean difference 49 min; 95% CI, –20 to 118; P = 0.151) when compared with placebo. However, adjunct lidocaine lessened the duration when compared with placebo (mean difference –212 min; 95% CI, –265 to –159; P < 0.001).

Neither perineural nor systemic dexamethasone affected the onset of the sensory or motor nerve block when compared with placebo. Lidocaine did not affect the onset of the sensory nerve block assessed by temperature discrimination but lessened the onset of the motor block. See table 1 for all outcome results.

No participants experienced serious adverse events or adverse events during the trial. All participants regained normal sensory and motor function.

We assessed if perineural dexamethasone as an adjunct to bupivacaine increased the duration of an ulnar nerve block when controlling for the systemic effects of the perineurally administered dexamethasone. Perineural dexamethasone resulted in a greater duration of the ulnar nerve block measured by temperature discrimination by a mean difference of 66 min (10.3% prolongation) when compared with placebo. Systemic dexamethasone had a duration similar to placebo measured by temperature discrimination. A post hoc linear mixed-effects model did not change the conclusions. We did not assess perineural and systemic dexamethasone for noninferiority because only perineural dexamethasone was statistically significantly superior to placebo.

This trial has several limitations. First, we used healthy volunteers without inflammation caused by surgical trauma or stress, which may limit the clinical relevance. The block-prolonging mechanism of action of adjunct dexamethasone has not been established, but one proposed mechanism is through anti-inflammation. This may explain the prolonged duration of analgesia of adjunct dexamethasone seen in most clinical trials, which we could not reproduce in this experimental setup. However, because we would expect any direct perineural effects of dexamethasone, not related to the anti-inflammation, to be apparent in healthy volunteers, we believe our trial has merits. To assess any potential direct perineural effect of dexamethasone, we found that the use of healthy volunteers was necessary, due to the infrequent use of bilateral surgery and due to the repetitive testing throughout the day and night, which would not have been ethical in a postsurgical setting. Second, we blocked a small nerve, which could potentially explain why the onset time was short for all treatment groups. Third, despite their relationship with the primary outcome, we did not adjust the threshold for statistical significance for the secondary outcomes. Therefore, the secondary outcomes should only be regarded as supportive of the primary outcome and for hypothesis generation. Fourth, we used a minimally important difference of 33% and a noninferiority margin of 25%. There are no generally accepted minimally important differences and noninferiority margins, and smaller differences and margins might also be important. However, previous trials used a similar minimally important difference and noninferiority margin as we used in this trial.^14,17 

Previous systematic reviews have shown that both perineural and systemic dexamethasone increases the duration of peripheral nerve blocks when compared with placebo.^1,3,6,7  This contrasts with our findings, that only perineural dexamethasone increased block duration, albeit not to a relevant extent. When comparing perineural and systemic dexamethasone directly in clinical trials, there is some clinical heterogeneity. One systematic review only found perineural dexamethasone to be superior to systemic dexamethasone when added to bupivacaine, while there was no evidence of a difference when added to ropivacaine.²  Another systematic review found evidence of perineural dexamethasone prolonging block duration by 241 min when compared with systemic dexamethasone.⁵  A third systematic review found no evidence of a difference between perineural and systemic dexamethasone.⁸  In a Cochrane review, systemic and perineural dexamethasone increased block duration to an identical degree when compared indirectly. However, when compared directly, perineural dexamethasone appeared to prolong block duration more than systemic dexamethasone.⁷  The difference in effects of perineural and systemic dexamethasone on block duration seems to range from no evidence of a difference to a potentially clinically relevant effect of perineural dexamethasone over systemic dexamethasone. However, none of the trials included in the systematic reviews have been able to control for the systemic effects of perineurally administered dexamethasone. Some authors have argued against the use of off-label perineural dexamethasone due to the limited advantage when compared with systemic administration.^2,5  Others have argued that more volunteer studies are needed to assess if perineural dexamethasone does increase the duration of peripheral nerve blocks.²⁰  We did not find evidence of a clinically relevant increase in block duration by perineural or systemic dexamethasone in healthy volunteers. Therefore, we did not assess for noninferiority of perineural versus systemic dexamethasone. The exact mechanism of action on block duration by dexamethasone remains unknown, but the effects could be mediated by the anti-inflammatory properties of dexamethasone.

Lidocaine can be added to long-acting local anesthetics such as bupivacaine or ropivacaine to shorten the onset time of the block in a clinical setting.^21,22  However, when we added lidocaine to bupivacaine, we did not find evidence of a decrease in time to onset, but the duration of the blocks was decreased substantially for all outcome measures.

Perineural dexamethasone as an adjunct to bupivacaine in healthy volunteers resulted in a greater duration of an ulnar nerve block when compared with placebo. Systemic dexamethasone resulted in a duration similar to placebo.

The Zealand Region of Denmark’s Research Fund funded the study and had no influence on the protocol, the conduct of the trial, data analyses, or writing of this manuscript.

The Department of Anesthesiology, Zealand University Hospital (Køge, Denmark) has received funding for other projects from The Novo Nordisk Foundation (Hellerup, Denmark) and Sygeforsikring DK (Copenhagen, Denmark), and conducted contract research for AM-Pharma (Utrecht, The Netherlands). The authors declare no other competing interests.

Supplemental Digital Content 1, Figure 3 – Perineural and placebo condition differences, https://links.lww.com/ALN/D107

Supplemental Digital Content 2, Figure 4 – Systemic and placebo condition differences, https://links.lww.com/ALN/D108

Supplemental Digital Content 3, Figure 5 – Lidocaine and placebo condition differences, https://links.lww.com/ALN/D109

Supplemental Digital Content 4, Figure 6 – Perineural and systemic condition differences, https://links.lww.com/ALN/D110