Peripheral nerve blockade (PNB) is a common regional anaesthetic technique with a large number of clinical indications. In daily practice, clinical PNB is used in a broad spectrum of surgical, interventional or diagnostic procedures. One unresolved problem associated with perioperative peripheral nerve block techniques is the limited duration of block and subsequent early demands for opioid-based analgesia, the latter with possible side effects on the central nervous, haemodynamic and respiratory systems.
Several approaches may increase the duration of nerve block. Continuous catheter techniques are one alternative, but these present the logistical challenge of continuous catheter observation and are associated with complications such as catheter displacement1 and infection.2–4 Alternatively, adjuvant drugs such as alpha-2 adrenergic receptor agonists, opioids, ketamine, dexamethasone and others can be used to increase block duration.5–14
Dexmedetomidine is a highly selective alpha-2 adrenergic receptor agonist. Experimental and clinical studies, with various doses between 20 and 150 μg as an additive to local anaesthetics, have been published.1,15–20 However, the optimal balance between long-lasting sensory block with a limited motor block and minimal side effects is still unknown. Recently, our group observed a 60% increase in the duration of sensory block when 20 μg of dexmedetomidine was added to ropivacaine 7.5 mg ml−1 for peripheral nerve block.21
In clinical practice, the rationale for the coadministration of dexmedetomidine with local anaesthetics for PNB is to prolong the time to first use of systemic analgesia. We therefore designed a prospective, randomised and triple-blinded volunteer study to evaluate the pharmacodynamic characteristics of ropivacaine alone, and when combined with three different doses of dexmedetomidine (50, 100 and 150 μg) for a single nerve block. A surrogate pharmacodynamic parameter (duration of sensory blockade) was used in the present study to evaluate an optimal dose of dexmedetomidine for peripheral nerve block.
Materials and methods
Ethical approval for this study (Ethical Committee No. 1849/2013) was provided by the Ethical Committee of the Medical University of Vienna, Borschkegasse 8b/6, A-1090 Vienna, Austria on 8 November 2013 and by the Austrian Agency for Health and Food Safety (EudraCT 2013-003790-10).
Healthy male volunteers, from 18 to 45 years of age, were screened to identify 24 eligible for the study. Volunteers who had been enrolled but dropped out before completion of the study day were replaced. Written informed consent was obtained from the volunteers after they had been provided with detailed information about the nature, risks and scope of the clinical study. Exclusion criteria included BMI more than 30 kg m−2, anatomical abnormalities of the forearm identified by physical examination, use of NSAIDs during the previous 2 weeks, known allergy or hypersensitivity to ropivacaine or other amino-amide local anaesthetics or dexmedetomidine, participation in another clinical study within the 4 weeks prior to study, coagulopathy, abnormalities of blood pressure (BP, hypotension with an SBP <90 mmHg or hypertension with an SBP >160 mmHg after 5 min resting), bradycardia with a heart rate (HR) less than 40 min−1, after 5 min resting and clinically relevant ECG abnormalities (heart block). After obtaining a detailed medical history, each volunteer underwent a general physical examination, which included HR and BP after 5 min resting supine. Blood samples were obtained for laboratory analyses, and an ECG was performed. At the screening visit, which took place within the 3 weeks before the study day, the volunteers were instructed to fast before the nerve block (6 h for solid food and 2 h for clear liquids).
Volunteers were randomised into four groups using an opaque envelope technique to receive an injectate volume of 4.5 ml of study solution:
The study drugs were prepared by a study nurse. Neither the anaesthetist performing the nerve blocks nor the volunteers were informed as to the identity of the study drug. Sensory tests and evaluation of sedation scores were performed by a study physician not otherwise involved in the study.
Ultrasound-guided ulnar nerve block
On the morning of the study day, the volunteers were admitted to the clinical research ward. An 18-gauge plastic cannula (Venflon) with a switch-valve was inserted into an antecubital vein (on the nonstudy arm).
The ulnar nerve was examined by ultrasound in the proximal forearm of the nondominant extremity. Here, the ulnar nerve lies between the flexor carpi ulnaris, the superficial flexor digitorum (humero-ulnar head) and flexor digitorum profundus muscles without any adjacent anatomic structures (e.g. blood vessels). The ultrasound appearance of the ulnar nerve in a transverse plane (short axis) in this position is hyperechoic and triangular or oval. Ultrasound imaging was performed using a SonoSite M-Turbo (SonoSite Inc., Bothell, Washington, USA) with an HFL 38 mm 15-6 MHz linear array transducer. After disinfection of the skin and sterile preparation of the ultrasound transducer, a 22-gauge, 50 mm, short-bevel facet tip ultrasound needle (Polymedic; te me na SAS, Carrie‘res sur Seine, France) was advanced under direct ultrasound visualisation in plane with the transducer. An extra-epineural multiinjection technique was used to create an almost circumferential spread of the study solution around the ulnar nerve.
- Primary outcome variable: Time from performance of the block to recovery of pinprick sensation to 100% in all sensory areas (complete recovery from sensory blockade).
- Secondary outcome variables: Successful blockade of the ulnar nerve (pinprick testing 0% in all sensory areas), onset time of sensory block of the ulnar nerve by pinprick testing; duration of total sensory block of the ulnar nerve by pinprick testing, onset time and duration of motor blockade; vigilance status evaluated by Richmond Agitation Sedation Scale (RASS),22 and haemodynamic parameters (HR and mean BP).
Sensory assessment was performed by pinprick testing in the area of the hand innervated by the ulnar nerve ipsilateral to the block, compared with the contralateral side (100%, normal sensation to 0%, no sensation). During sensory assessment, the tip of the needle (22-G short bevel) was applied to the skin with a force that was adequate to indent the skin but not enough to puncture it in order to produce a consistent painful sensation when applied to the areas with normal sensation. Sensory scores were evaluated at the following times: prior the block, 2, 4, 6, 8, 10, 15, 20, 30 and 60 min, after the block and then every 30 min until complete recovery. Five areas were marked in the hand for assessment of the sensory block: dorsal side hypothenar muscles, ulnar side hypothenar area, palmar side hypothenar muscles, fifth finger and ulnar side fourth finger.
Motor score testing
Motor scores were evaluated simultaneously with the sensory scores and were defined as the ability of thumb adduction in comparison with the contralateral side where:
- 3, no difference, adduction against resistance possible.
- 2, slight difference, adduction against slight resistance hardly possible.
- 1, marked difference, adduction without resistance hardly possible.
- 0, no active adduction possible, paralysis.
Richmond Agitation Sedation Scale
The Richmond Agitation Sedation Scale22 was used for monitoring of sedation level (Table 1) at the same time points when sensory scores were evaluated.
Definition of time points (h)
- Sensory block onset time: time from performance of the block to pinprick 0% in all sensory areas.
- Duration of sensory block: time during which pinprick 0% persisted in all areas.
- Complete recovery from sensory block: time from performance of the block to pinprick 100% in all sensory areas.
- Motor block onset time: time from performance of the block to a motor score of 0.
- Duration of motor block: time during which motor score 0 persisted.
- Time to maximum sedation level: time from performance of the block to the maximum sedation level (RASS score).
Safety monitoring and safety management
The volunteers were monitored (ECG, SpO2 and NIBP) before and during the performance of the block and until complete resolution of the ulnar nerve block. Bradycardia was defined as reduction of HR to less than 40 min−1. In those cases, 0.01 mg kg−1 glycorpyrrolate (Robinul) was administered. Hypotension was defined as a reduction of mean BP of more than 25% of initial measurement and was treated with rapid intravenous (i.v.) administration of 500 ml of the balanced crystalloid infusion solution (Elomel isoton) and, if this treatment was insufficient, with repeated 2 mg doses of the sympathomimetic amine, etilefrine (Effortil), until stabilisation. Those volunteers in whom a decrease in SpO2 less than 90% due to sedation with dexmedetomidine occurred were physically stimulated. An emergency telephone number enabled the volunteers to contact the team in cases of any medical problems after discharge. Within 1 week after the study, all volunteers were examined in the clinic by a physician for any clinical signs of ulnar nerve injury, local inflammation or infection at the skin puncture site.
Data are presented as median (range) or mean (SD). No formal sample size calculation was performed, as the study was designed for a mainly descriptive evaluation of four different study groups. As primary and secondary outcomes consist of time-to-event data, logrank test analyses were performed and the dose-dependency of dexmedetomidine was evaluated with the logrank test for trend. The dose-dependent effects of dexmedetomidine on sedation scores were analysed using the Cuzick trend test. Other data were analysed using a Kruskal–Wallis one-way analysis and unpaired Mann–Whitney U-posthoc tests with Bonferroni–Holm correction. IBM SPSS Statistics 20.0 (IBM Inc., Armonk, New York, USA) and GraphPad Prism (GraphPad Software, Inc., La Jolla, California, USA) were used for analysis and P value of 0.05 or less was considered as statistically significant.
We investigated 24 volunteers in four study groups of six. One volunteer was replaced due to withdrawal of informed consent. The CONSORT flow diagram is shown in Fig. 1. Age and BMIs were comparable between the study groups (Table 2). All the ultrasound-guided ulnar nerve blocks were successful with pinprick testing scores of 0% in all sensory areas.
The block onset time was decreased significantly in a dose-dependent manner (P < 0.05). A statistically significant dose-dependent increase in both duration of sensory blockade and the time to complete recovery was observed with dexmedetomidine (P < 0.0001) (Fig. 2). Motor block onset time was unaffected by the dose of dexmedetomidine, whereas the duration of motor block was significantly increased (P < 0.05). Detailed nerve block characteristics are summarised in Table 2. There were three volunteers with remarkably long sensory block onset times, two in group R (2 and 2.5 h) and one in group RD50 (1.5 h). Perineural application of dexmedetomidine caused clinically relevant sedation in a dose-dependent manner (P < 0.001, Cuzick trend test, Fig. 3). The maximum sedation score was −4, observed in two volunteers in group RD150.
Low BP occurred in eight volunteers: one (R), one (RD50), two (RD100), four (RD150). Compared with the preblock levels, the mean BP fall in each group was 15 (21) (R), -20 (12) (RD50), 25 (9) (RD100) and 28 (12) mmHg (RD150). None of these changes reached statistical significance. Compared with preblock values, the fall in HR was 11 min−1 (eight) in group R, 21 min−1 (11) in group RD50, 19 min−1 (five) in group RD100 and 16 min−1 (eight) in group RD150 (P < 0.05 in both group R versus group RD50 and group R versus group RD100). Apart from in one volunteer in group RD50 in whom the HR dropped to 38 min−1 2 h after nerve blockade, other haemodynamic alterations were clinically unremarkable.
After an apparent initial complete recovery from sensory blockade, two volunteers in group RD150 reported recurring discrete paraesthesiae in the sensory supply area of the ulnar nerve. These resolved completely after 72 h. No other side effects were observed throughout the study period or at the follow-up examination.
Three different doses of dexmedetomidine as an adjuvant drug to 22.5 mg ropivacaine for PNB were investigated in this volunteer study. The main findings were that dexmedetomidine exhibited dose-dependent increases in duration of, and recovery from, sensory nerve block. Likewise, and consistent with the expected pharmacology, there were similar effects on sedation. The maximum dose of dexmedetomidine in this study (150 μg) was associated with deep sedation and prolonged paraesthesiae. Thus, our data suggest a clinical evaluation of dexmedetomidine doses between 20 and 100 μg for peripheral nerve blocks. According to our results, a dose of 100 μg dexmedetomidine seems to have a good balance between prolongation of nerve block and the intensity of sedation.
Currently, dexmedetomidine is mainly used for sedation in anaesthesia and intensive care medicine and is approved only for these indications. The mechanism by which alpha-2 adrenergic receptor agonists produce analgesia and sedation is multifactorial and described in detail elsewhere.21 The clinical effect of dexmedetomidine as an adjuvant drug for regional anaesthesia has been investigated in animal, experimental and clinical studies. Using various long-acting local anaesthetic drugs in rats, Brummett et al.23,24 reported that dexmedetomidine prolonged the duration of sciatic nerve block. Our previous study in volunteers showed that perineural block with 20 μg dexmedetomidine and ropivacaine 7.5 mg ml−1 for a single nerve block increased the duration of a total sensory block by nearly 60% compared with plain local anaesthetic [555 (118) versus 350 (54) min, P < 0.01].21 This prolongation of peripheral nerve block is mainly caused by a local neuronal mechanism because the systemic administration of the same dose of dexmedetomidine resulted in only a 10% increase of nerve block duration. This perineural mechanism has also been confirmed by Brummett et al.25 in animals. A recent review article confirms that dexmedetomidine prolongs the duration of local anaesthetic both for central and peripheral regional anaesthetic techniques.26
Some clinical studies have investigated different doses of dexmedetomidine (30 to 150 μg) for PNB (Table 3), but the optimal dose to provide a balance between the maximum analgesic effect while limiting side effects is still not defined. Brummett et al.29 have shown dose-dependent increasing analgesic effects of perineural dexmedetomidine (0.5, 2, 6 and 20 μg kg−1) for sciatic nerve blockade in rats. Nevertheless, due to the dual clinical effects of analgesia and sedation with dexmedetomidine, the determination of optimal doses for use as adjuvants for local anaesthetic in PNB is an important scientific question. Our data also suggest faster sensory block onset with increased doses of dexmedetomidine. We observed three unexpectedly long sensory onset times in the R and RD50 study groups. A possible explanation for such long onset times was the strict evaluation for sensory block used in this study, as pinprick scores had to be 0% in all nerve supply areas tested.
The local tissue toxicity of perineural dexmedetomidine has been investigated in animal studies and shows that the nerve axon and myelin were unaffected after 24 h and 14 days.24,29 Nevertheless, in two volunteers receiving 150 μg dexmedetomidine, we observed prolonged (72 h) paraesthesiae in the sensory supply area of the ulnar nerve, an observation that requires consideration. Intraneural administration of local anaesthetic is unlikely given the strict ultrasound-guided extra-epineural needle tip position and subsequent extra-epineural administration of the study solution. Thus, a direct relation between the prolonged paraesthesia and higher dose perineural dexmedetomidine is a definite possibility.
Similar to previous studies,16,18 we observed discrete alterations in haemodynamic variables when dexmedetomidine was administered. But it should also be noted that BP decreased in the ropivacaine-only control group. This may be due to anxiety of the volunteers prior to nerve blockade. In one volunteer in the RD50 group, the HR slowed to 38 beats min−1. Compared with group R, there were significant decreases in HR in both groups RD50 and RD100. As expected, we observed higher sedation levels with increasing doses of dexmedetomidine. Two volunteers in the RD150 study group attained a sedation score of -4 (deep sedation requiring physical stimulation). This finding in young healthy volunteers could pose a serious clinical risk to older and sick patients.
There are some limitations to our study. We investigated only six volunteers in each study group. Volunteer studies are costly and therefore a balance between low numbers of volunteers and the power of the results is required. However, volunteer studies are associated with the obvious advantage of a consistent experimental setting. Also, the absence of surgery is an advantage in that side effects can be correctly attributed to the intervention. The block of a single sensory nerve, and not pain, was evaluated in this nonclinical setting in a young and healthy study population. Differences may exist in the pharmacodynamics and efficacy with regard to other nerve blocks and these require similar investigations of safety and efficacy.
In summary, this volunteer study showed that dexmedetomidine increased the duration of sensory block in a dose-dependent manner. The use of 150 μg dexmedetomidine caused deep sedation or postblock paraesthesiae in one-third of the patients. Subsequent clinical studies should consider this fact, and perhaps limit the upper dose of dexmedetomidine to 100 μg for regional anaesthesia in other settings and patient populations.
Acknowledgements relating to this article
Assistance with the study: we thank Beatrix Wulkersdorfer (Clinical Pharmacologist, Medical University of Vienna, Department of Clinical Pharmacology, Vienna, Austria), Heimo Lagler (Staff member, Medical University of Vienna, Department of Internal Medicine and Department of Clinical Pharmacology, Vienna, Austria), Andjela Bäwert (Staff member, Medical University of Vienna, Department of Psychiatry and Psychotherapy and Department of Clinical Pharmacology, Vienna, Austria) and Edith Lackner (Registered nurse, Study nurse, Medical University of Vienna, Department of Clinical Pharmacology, Vienna, Austria) for their support during the practical performance of the cases. This work was performed at the Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria. M Keplinger, P Marhofer, SC Kettner and M Zeitlinger contributed to the conception and design of the study, analysis, interpretation of the data and drafting of the manuscript. M Zeitlinger contributed to the acquisition of the cases. M Keplinger, P Marhofer, D Marhofer and M Zeitlinger contributed to the practical performance of the blocks. O Kimberger and SC Kettner conducted the statistical analyses.
Financial support and sponsorship: this work was supported by departmental sources only.
Conflicts of interest: PM has received honoraria from SonoSite Inc., unrestricted grants from Pajunk Inc. and BBraun Inc. and is member of the editorial boards of the British Journal of Anaesthesia and Pediatric Anesthesia.
1. Marhofer D, Marhofer P, Triffterer L, et al. Dislocation rates of perineural catheters: a volunteer study. Br J Anaesth
2. Aveline C, Le Hetet H, Le Roux A, et al. Perineural ultrasound-guided catheter bacterial colonization: a prospective evaluation in 747 cases. Reg Anesth Pain Med
3. Compère V, Rey N, Baert O, et al. Major complications after 400 continuous popliteal sciatic nerve blocks for postoperative analgesia. Acta Anaesthesiol Scand
4. Ilfeld BM. Continuous peripheral nerve blocks: a review of the published evidence. Anesth Analg
5. Axelsson K, Gupta A. Local anaesthetic adjuvants: neuraxial versus peripheral nerve block. Curr Opin Anaesthesiol
6. Bernard JM, Macaire P. Dose-range effects of clonidine added to lidocaine for brachial plexus block. Anesthesiology
7. Casati A, Magistris L, Fanelli G, et al. Small-dose clonidine prolongs postoperative analgesia after sciatic-femoral nerve block with 0.75% ropivacaine for foot surgery. Anesth Analg
8. Erlacher W, Schuschnig C, Koinig H, et al. Clonidine as adjuvant for mepivacaine, ropivacaine and bupivacaine in axillary, perivascular brachial plexus block. Can J Anaesth
9. Hutschala D, Mascher H, Schmetterer L, et al. Clonidine added to bupivacaine enhances and prolongs analgesia after brachial plexus block via a local mechanism in healthy volunteers. Eur J Anaesthesiol
10. Magistris L, Casati A, Albertin A, et al. Combined sciatic-femoral nerve block with 0.75% ropivacaine: effects of adding a systemically inactive dose of fentanyl. Eur J Anaesthesiol
11. Trifa M, Ben Khalifa S, Jendoubi A, et al. Clonidine does not improve quality of ropivacaine axillary brachial plexus block in children. Paediatr Anaesth
12. Weber A, Fournier R, van Gessel E, et al. Epinephrine does not prolong the analgesia of 20 mL ropivacaine 0.5% or 0.2% in a femoral three-in-one block. Anesth Analg
13. Vieira PA, Pulai I, Tsao GC, et al. Dexamethasone with bupivacaine increases duration of analgesia in ultrasound-guided interscalene brachial plexus blockade. Eur J Anaesthesiol
14. Choi S, Rodseth R, McCartney CJ. Effects of dexamethasone as a local anaesthetic adjuvant for brachial plexus block: a systematic review and meta-analysis of randomized trials. Br J Anaesth
15. Ammar AS, Mahmoud KM. Ultrasound-guided single injection infraclavicular brachial plexus block using bupivacaine alone or combined with dexmedetomidine for pain control in upper limb surgery: a prospective randomized controlled trial. Saudi J Anaesth
16. Esmaoglu A, Yegenoglu F, Akin A, Turk CY. Dexmedetomidine added to levobupivacaine prolongs axillary brachial plexus block. Anesth Analg
17. Gandhi R, Shah A, Patel I. Use of dexmedetomidine along with bupivacaine for brachial plexus block. Natl J Med Res
18. Kaygusuz K. Effects of adding dexmedetomidine to levobupivacaine in axillary brachial plexus block. Curr Ther Res Clin Exp
19. Rutkowska K, Knapik P, Misiolek H. The effect of dexmedetomidine sedation on brachial plexus block in patients with end-stage renal disease. Eur J Anaesthesiol
20. Swami SS, Keniya VM, Ladi SD, Rao R. Comparison of dexmedetomidine and clonidine (α2 agonist drugs) as an adjuvant to local anaesthesia in supraclavicular brachial plexus block: a randomised double-blind prospective study. Indian J Anaesth
21. Marhofer D, Kettner SC, Marhofer P, et al. Dexmedetomidine as an adjuvant to ropivacaine prolongs peripheral nerve block: a volunteer study. Br J Anaesth
22. Sessler CN, Gosnell M, Grap MJ, et al. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care patients. Am J Respir Crit Care Med
23. Brummett CM, Hong EK, Janda AM, et al. Perineural dexmedetomidine added to ropivacaine for sciatic nerve block in rats prolongs the duration of analgesia by blocking the hyperpolarization-activated cation current. Anesthesiology
24. Brummett CM, Norat MA, Palmisano JM, Lydic R. Perineural administration of dexmedetomidine in combination with bupivacaine enhances sensory and motor blockade in sciatic nerve block without inducing neurotoxicity in rat. Anesthesiology
25. Brummett CM, Amodeo FS, Janda AM, et al. Perineural dexmedetomidine provides an increased duration of analgesia to a thermal stimulus when compared with a systemic control in a rat sciatic nerve block. Reg Anesth Pain Med
26. Abdallah FW, Brull R. Facilitatory effects of perineural dexmedetomidine on neuraxial and peripheral nerve block: a systematic review and meta-analysis. Br J Anaesth
27. Rancourt MM, Albert NT, Côté M, et al. Posterior tibial nerve sensory blockade duration prolonged by adding dexmedetomidine to ropivacaine. Anesth Analg
28. Fritsch G, Danninger T, Allerberger K, et al. Dexmedetomidine added to ropivacaine extends the duration of interscalene brachial plexus blocks for elective shoulder surgery when compared with ropivacaine alone: a single-center, prospective, triple-blind, randomized controlled trial. Reg Anesth Pain Med
29. Brummett CM, Padda AK, Amodeo FS, et al. Perineural dexmedetomidine added to ropivacaine causes a dose-dependent increase in the duration of thermal antinociception in sciatic nerve block in rat. Anesthesiology