13652044, 2016, 10, Downloaded from https://associationofanaesthetists-publications.onlinelibrary.wiley.com/doi/10.1111/anae.13603, Wiley Online Library on [06/03/2023].

See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Anaesthesia 2016, 71, 1177–1185 doi:10.1111/anae.13603

Original Article
The effects of perineural dexmedetomidine on the
pharmacodynamic profile of femoral nerve block: a dose-finding
randomised, controlled, double-blind study
M. Abdulatif,1 M. Fawzy,1 H. Nassar,2 A. Hasanin,2 M. Ollaek3 and H. Mohamed3

1 Professor, 2 Lecturer, 3 Assistant Lecturer, Anaesthetic Department, Faculty of Medicine, Cairo University, Cairo,
Egypt

Summary
This randomised, controlled, double-blind study investigated the effects of different doses of perineural dexmedeto-
midine on the pharmacodynamic profile of femoral nerve block in patients undergoing arthroscopic knee surgery.
Ultrasound-guided femoral nerve block was performed before general anaesthesia using 25 ml of bupivacaine 0.5%
combined with normal saline in the control group, and 25 lg, 50 lg or 75 lg of dexmedetomidine in three treat-
ment groups (n = 15 for each group). All patients received a standard general anaesthetic and multimodal postopera-
tive analgesic regimen. The use of the 50 lg and 75 lg dose levels of dexmedetomidine was associated with
reduction of the onset time, extension of the duration of block, prolonged time to the first postoperative request for
rescue analgesia, and reduced postoperative morphine requirements. The times to first request for postoperative anal-
gesia were mean (SD) 10.8 (1.6) h in the control group and 11.0 (7.1), 21.8 (3.0) and 28.6 (10.0) in the 25 lg, 50 lg
and 75 lg treatment groups, respectively. These times were significantly longer in the 50 lg and 75 lg treatment
groups compared with the 25 lg (p < 0.0001) and control group (p < 0.0001). The total 24-h postoperative mor-
phine consumption was 7.6 (5.1) mg in the control group, and 6.5 (3.5), 3.9 (3.4), 1.8 (2.6) in the 25 lg, 50 lg and
75 lg treatment groups, respectively. Postoperative morphine consumption was significantly higher in the control
group compared with the 50 lg (p = 0.045) and the 75 lg (p = 0.001) treatment groups. The best analgesic profile
was achieved at the 75 lg dose, but this was associated with increased risk of hypotension.
.................................................................................................................................................................
Correspondence to: M. Abdulatif
Email: [email protected]
Accepted: 17 June 2016
Keywords: adrenergic alpha-2 receptor agonists; anaesthetics; bupivacaine; dexmedetomidine; femoral; local; peripheral
nerves

Introduction postoperative opioids. Many adjuvants have been

Peripheral nerve blocks are frequently used as the sole added to prolong the duration of nerve blocks [3].
anaesthetic technique or as an adjuvant to general Alpha-2 adrenoceptor agonists have been shown to
anaesthesia [1, 2]. However, the duration of sensory increase the duration of peripheral nerve blocks in
block after single doses of long-acting local anaesthet- adults [4] and in children [5]. Perineural dexmedeto-
ics is not consistent enough to avoid the use of midine prolonged the duration of nerve block with no

© 2016 The Association of Anaesthetists of Great Britain and Ireland 1177

 13652044, 2016, 10, Downloaded from https://associationofanaesthetists-publications.onlinelibrary.wiley.com/doi/10.1111/anae.13603, Wiley Online Library on [06/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Anaesthesia 2016, 71, 1177–1185 Abdulatif et al. | Dose–response of dexmedetomidine and femoral nerve block

evidence of neurotoxicity for up to 14 days after initial assessed study outcomes were all blinded to study
administration in animal model [6]. There are also group allocation. The study drugs were prepared by an
studies that have evaluated the effectiveness of investigator who was not involved in either block per-
dexmedetomidine in augmenting the duration of bra- formance or outcome assessment.
chial plexus block for upper limb surgery [7]. In con- No premedication or sedation was given to any
trast, the use of dexmedetomidine for peripheral nerve participant. Peripheral intravenous access was secured,
block in lower limb surgery has not been adequately and peri-operative monitoring included ECG, non-
investigated. A recent study reported significantly invasive arterial blood pressure and pulse oximetry.
increased duration of combined femoral and sciatic Ultrasound-guided femoral nerve block was performed
nerve block with the use of a single dose of 100 lg of before induction of general anaesthesia by a single
dexmedetomidine [8]. A dose-finding study in volun- trained investigator. With the patient in the supine
teers reported deep sedation with the use of 150 lg position and after disinfection of the skin in the ingu-
dexmedetomidine as an adjuvant to ropivacaine- inal region and upper thigh, the femoral nerve was
induced ulnar nerve block, and recommended a maxi- located using a linear multifrequency 13–6 MHz ultra-
mum dose of 100 lg [9]. Marhofer and Brummett sound probe (ACUSON X300, 10037409; Siemens
[10] recently suggested that, based on current evidence, Medical Solutions, California City, CA, USA) in a
perineural dexmedetomidine is the most promising transverse plane at the inguinal crease, lateral to the
adjuvant to extend the duration of long-acting local pulsation of the femoral artery. A 22 G, 50 mm, short-
anaesthetics. However, the dose needed to achieve an bevel Stimuplex D needle (B. Braun, Melsungen AG,
optimal balance between block duration, haemody- Germany) was advanced under direct ultrasound visu-
namic side-effects and sedation in clinical practice has alisation, in-plane with the transducer in a short axis.
yet to be identified [10]. A multiple injection technique was used, with the tip
This double-blind, randomised, controlled study of the needle in several positions around the nerve.
was designed to explore and compare the effects of dif- The designated volume of a local anaesthetic combined
ferent dose levels of perineural dexmedetomidine on with the study medication was injected under sono-
the pharmacodynamic profile of bupivacaine-induced graphic visualisation, strictly within the fascial space
femoral nerve block. Our study groups comprised and as close as possible to the femoral nerve. The fol-
patients undergoing arthroscopic anterior cruciate liga- lowing injectates were given according to patient’s
ment reconstruction under general anaesthesia. study group assignment: 25 ml bupivacaine 0.5%, plus
1 ml normal saline (control group); 25 ml bupivacaine
Methods 0.5%, plus 25 lg, 50 lg or 75 lg dexmedetomidine
The study received approval from our Institutional Eth- (study groups). The total volume of dexmedetomidine
ical Committee before patient enrolment. was adjusted to 1 ml to ensure that the same volume
Adult patients aged 18–45 years, ASA physical sta- of injectate was used in all groups and to aid operator
tus 1 or 2 who were scheduled for arthroscopic ante- blinding.
rior cruciate ligament reconstruction were recruited, An investigator blinded to the nature of the injec-
and written informed consent was obtained. Exclusion tate assessed sensory block with a pinprick test over a
criteria were: peripheral neuropathy; renal or hepatic period of 30 min after injection of the study medica-
dysfunction; inflammation or infection at the puncture tions using a 3-point scale: 0 = complete loss of sensa-
site; history of allergic reaction to any of the study tion, 1 = partial loss of sensation and 2 = normal
medications. sensation [9]. The pinprick test compared sensation in
An online randomisation program (http:// the contralateral area at the sensory distribution of the
www.randomizer.org) was used to allocate each patient femoral nerve. Motor (quadriceps) block was evaluated
into one of the four study groups by means of random by grading patients’ ability to perform a straight leg
numbers concealed in sealed opaque envelopes. The raise test. Motor block was classified as: grade 0, nor-
patients, operator performing the block and those who mal muscle power; grade 1, motor weakness; grade 2,

1178 © 2016 The Association of Anaesthetists of Great Britain and Ireland

 13652044, 2016, 10, Downloaded from https://associationofanaesthetists-publications.onlinelibrary.wiley.com/doi/10.1111/anae.13603, Wiley Online Library on [06/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Abdulatif et al. | Dose–response of dexmedetomidine and femoral nerve block Anaesthesia 2016, 71, 1177–1185

complete motor paralysis [11]. Sensory and motor block, every 15 min intra-operatively, and every 2 h
blocks were assessed every 5 min for the first 30 min, postoperatively for a period of 8 h. Hypotension was
then postoperatively every 2 h until the return of nor- defined as a 30% decrease in systolic arterial blood
mal sensory and motor functions. pressure from the baseline value, and was treated with
Onset time for sensory and motor block was incremental doses of intravenous ephedrine 6 mg, as
defined as the time interval between the end of injec- required. Bradycardia, defined as heart rate less than
tion and the development of complete sensory and 50 min 1, was treated with intravenous atropine 0.5–
motor block. Duration of sensory and motor block 1.0 mg. Desaturation (SpO2 < 90% on room air) was
was defined as the time interval between the end of managed by stimulating the patient and administering
injection and complete resolution of sensory and supplemental oxygen. Episodes of postoperative nausea
motor block. In the postoperative period, the skin der- and/or vomiting were recorded and managed with
matomes covered by the surgical dressing were not ondansetron.
accessible to pinprick testing. Therefore, the time to The primary outcome measure of this study was
first postoperative request for rescue analgesia (mor- duration of sensory block. A previous volunteer study
phine) was used as the surrogate end-point for the [13] in which ropivacaine and dexmedetomidine
duration of sensory block. 1 lg.kg 1 was used for posterior tibial nerve block,
After ensuring successful femoral nerve block, reported a difference in mean duration of sensory
patients were transferred to the operating room to block of 5.3 h between the control and dexmedeto-
receive a standardised general anaesthetic. Anaesthesia midine groups, with a standard deviation of 2 h and
was induced with fentanyl 2 lg.kg 1, propofol 1.5– 1.2 h, respectively. We made a more conservative
2.5 mg.kg 1, and atracurium 0.5 mg.kg 1 to facilitate assumption, increasing the standard deviations by 60%
insertion of an appropriately sized laryngeal mask air- to improve precision of the sample size estimation [14,
way. Anaesthesia was maintained with isoflurane, end- 15]. Power analysis was performed using analysis of
tidal concentration 1–2%, to keep systolic arterial variance for independent samples. At a power of 0.95
blood pressure and heart rate within 20% of baseline and an alpha error of 0.01, we calculated that a mini-
values. Mechanical ventilation was adjusted to main- mum sample size of 13 patients was required for each
tain normocapnia. At the end of the operation, isoflu- of the four study groups. This was increased to 15
rane was discontinued, and residual neuromuscular patients to allow for possible dropouts.
block was reversed using neostigmine and atropine. One-way analysis of variance was used to compare
All patients received a combination of intravenous differences between groups. Repeated measure
paracetamol 1 g and ketorolac 30 mg at the conclusion ANOVA was used for intra-group comparisons. Chi-
of surgery. This regimen was repeated regularly every square or Fisher's exact tests were used to compare the
8 h. Visual analogue pain scores (VAS) were assessed frequency of adverse effects. Kaplan–Meier survival
at 2, 4, 6, 8, 12, 16 and 24 h postoperatively. Persistent curves were constructed to compare time to first
or breakthrough pain was managed with 2 mg incre- request for postoperative analgesia between groups.
mental doses of intravenous morphine to maintain a p < 0.05 was regarded as statistically significant. PASS
resting VAS at ≤ 3, and the total 24-h morphine con- 14 (Kaysville, UT, USA) was used for sample size esti-
sumption was recorded. The time to first request of mation and SPSS 15 (Chicago, IL, USA) for data anal-
rescue postoperative analgesic was defined as the time ysis.
interval between the onset of successful sensory block
and the first request to postoperative morphine. The Results
Richmond Agitation Sedation Score (RASS) [12] was Sixty-five patients fulfilled the inclusion criteria. Five
assessed 15 min and 30 min after injection of study patients were not studied due to failed block, so 60
medications, and every hour for 8 h postoperatively. patients completed the study (Fig. 1). Patient charac-
Heart rate, arterial blood pressure and SpO2 were teristics were similar in the four study groups
recorded before, 15 min, 30 min after femoral nerve (Table 1).

© 2016 The Association of Anaesthetists of Great Britain and Ireland 1179

 13652044, 2016, 10, Downloaded from https://associationofanaesthetists-publications.onlinelibrary.wiley.com/doi/10.1111/anae.13603, Wiley Online Library on [06/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Anaesthesia 2016, 71, 1177–1185 Abdulatif et al. | Dose–response of dexmedetomidine and femoral nerve block

The 25 lg dose of dexmedetomidine did not modify Sensory block onset time was shorter in the 50 lg
the pharmacodynamic profile of bupivacaine-induced and 75 lg groups than the 25 lg group (p < 0.0001) or
femoral nerve block when compared with the control. control group (p < 0.0001). Time to first request for

Figure 1 CONSORT flow diagram showing number of patients at each phase of the study.

1180 © 2016 The Association of Anaesthetists of Great Britain and Ireland

 13652044, 2016, 10, Downloaded from https://associationofanaesthetists-publications.onlinelibrary.wiley.com/doi/10.1111/anae.13603, Wiley Online Library on [06/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Abdulatif et al. | Dose–response of dexmedetomidine and femoral nerve block Anaesthesia 2016, 71, 1177–1185

Table 1 Patient characteristics in the four study groups. Values are mean (SD) or number.

Control Dexmedetomidine 25 lg Dexmedetomidine 50 lg Dexmedetomidine 75 lg

Data n = 15 n = 15 n = 15 n = 15
Age; years 27.9 (7.3) 28.2 (8.6) 31.7 (7.9) 27.4 (6.4)
Weight; kg 72.6 (10.8) 73.6 (7.9) 75.8 (6.3) 70.3 (9.6)
Sex; male 13 15 15 12
ASA physical 13/2 14/1 14/1 14/1
status; 1/2

rescue postoperative analgesia was longer in the 50 lg study groups at the same time assessment points, but
and 75 lg groups compared with the 25 lg groups episodes of hypotension were significantly more com-
(p < 0.0001) and control (p < 0.0001) (Table 2). The mon in the 75 lg group compared with the other
75 lg dose of dexmedetomidine was associated with the three groups (p = 0.002). Incidence of intra-operative
longest duration of sensory block and the longest time bradycardia was also comparable between groups
to first request for rescue analgesia (Fig. 2). (Table 2).
Motor block onset time was also shorter in the Postoperative pain scores (as measured by a visual
50 lg and 75 lg groups when compared with control analogue scale) were ≤ 3 using the multimodal anal-
(p = 0.004, p < 0.0001, respectively), and between the gesic regimen supplemented by intravenous morphine
25 lg and 75 lg groups (p = 0.003). Duration of as rescue analgesia. Total postoperative morphine
motor block was longer in the 75 lg group compared requirement was lower in the 75 lg (p = 0.001) and
with other study groups (p < 0.0001), and was longer 50 lg groups (p = 0.045) than in the control group.
in the 50 lg group compared with control (p = 0.001). Postoperative morphine requirement was also lower in
Richmond Agitation Sedation Scores were compa- the 75 lg group (p = 0.007) than in the 25 lg group
rable in the four study groups, both before induction (Table 2).
of general anaesthesia and during the recovery period. We did not encounter any complications related
There were no episodes of desaturation. Pre-operative to femoral nerve block such as neuropraxia, vascular
and intra-operative changes in systolic arterial blood puncture, allergy to local anaesthetics or local infec-
pressure and heart rate were comparable in the four tion.

Table 2 Femoral nerve block characteristics and incidence of haemodynamic side-effects. Values are mean (SD) or
number (proportion).

Dexmedetomidine Dexmedetomidine Dexmedetomidine

Control 25 lg 50 lg 75 lg
Data n = 15 n = 15 n = 15 n = 15
Onset of sensory block; min 10.6 (1.7) 9.0 (2.9) 5.8 (1.4)*,† 4.3 (0)*,†
Duration of sensory block; h 21.6 (3.0) 23.3 (1.8) 30.8 (3.6)*† 43.7 (4.3)*,†,‡
Onset of motor block; min 13.6 (2.8) 12.4 (1.7) 10.7 (1.6)* 9.4 (2.3)*,†
Duration of motor block; h 13.6 (1.2) 15.4 (4.0) 19.4 (2.4)* 36.1 (6.4)*,†,‡
Time to first request to rescue 10.8 (1.6) 11.0 (7.1) 21.8 (3.0)*,† 28.6 (10.0)*,†,‡
postoperative analgesia; h
Total 24 h postoperative 7.6 (5.1) 6.5 (3.5) 3.9 (3.4)* 1.8 (2.6)*,†
morphine consumption; mg
Incidence of bradycardia; n 7 (46%) 4 (27%) 6 (40%) 3 (20%)
Incidence of hypotension; n 3 (20%) 4 (27%) 4 (27%) 12 (80%)*,†,‡

*Statistical significance compared with the control group.

†Statistical significance compared with 25 lg group.
‡Statistical significance compared with 50 lg group.

© 2016 The Association of Anaesthetists of Great Britain and Ireland 1181

 13652044, 2016, 10, Downloaded from https://associationofanaesthetists-publications.onlinelibrary.wiley.com/doi/10.1111/anae.13603, Wiley Online Library on [06/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Anaesthesia 2016, 71, 1177–1185 Abdulatif et al. | Dose–response of dexmedetomidine and femoral nerve block

20 lg to 150 lg [17, 18]. The only dose–response

study for the use of dexmedetomidine as an adjuvant
to local anaesthetic-induced ulnar nerve block was
conducted in volunteers, and concluded that the
100 lg dose level may represent an optimal balance
between efficacy and sedation [9]. Our clinical study is
the first to compare the potentiating effects of three
doses of perineural dexmedetomidine on femoral nerve
block in patients undergoing arthroscopic knee sur-
gery. Our study findings confirm earlier data from bra-
chial plexus studies [7]. However, in contrast to our
negative results with the use of the low 25 lg dose
Figure 2 Kaplan–Meier curve for duration of analgesia. level, Marhofer et al. [17] reported almost 60% exten-
Pooled Log rank test p < 0.001. Dexmedetomidine sion of the duration of ropivacaine-induced ulnar
75 lg group (s), Dexmedetomidine 50 lg group (&),
nerve block with the use of 20 lg perineural
Dexmedetomidine 25 lg group (h), Control group

( ). dexmedetomidine in volunteers. This difference could
be related to the type and size of the nerve to be
Discussion blocked [19, 20], the type of local anaesthetic used [21,
We have shown that, within the context of multimodal 22] and the study population; volunteers rather than
analgesia, the use of 50 lg and 75 lg perineural patients [23].
dexmedetomidine is associated with a reduction in Dexmedetomidine extended the duration of sen-
onset time, extension of the duration of bupivacaine- sory block more than duration of motor block. Experi-
induced femoral nerve block, prolonged time to the mental studies on dexmedetomidine as an adjuvant for
first request for rescue postoperative analgesia and nerve blocks have shown that duration of analgesia is
reduced postoperative morphine requirements. Dura- prolonged by blocking the hyperpolarisation-activated
tion of sensory block was longer than motor block. cation current (Ih current) [24]. Blocking the Ih cur-
Hypotensive episodes were more commonly encoun- rent results in prolonged hyperpolarisation of the
tered with the use of the 75 lg dose level. The lowest nerve, which seems to be more pronounced in
(25 lg) dose level of dexmedetomidine did not poten- unmyelinated C fibres (pain) than in Aa fibres (motor)
tiate bupivacaine-induced femoral nerve block. [24]. Blocking the Ih current may therefore have a
Our results are generally in line with a recent more pronounced effect on pain than motor response
meta-analysis which confirmed the effectiveness of per- [25].
ineural dexmedetomidine in extending the duration of An interesting finding of our study is the longer
brachial plexus block [7]. Furthermore, experimental duration of dermatomal sensory block compared with
studies on the femoral nerve in dogs [16] and the pos- the time to first request for rescue analgesia. This
terior tibial nerve in volunteers [13] reported signifi- result is not consistent with previous studies in upper
cant prolonged sensory block with the addition of limb surgical procedures [26, 27]. Anatomically, an
1 lg.kg 1 dexmedetomidine. However, it is difficult to effective brachial plexus block at the root level would
extrapolate results from experimental or volunteer data be expected to provide adequate peri-operative anaes-
to the clinical setting. A recent clinical study reported thesia and analgesia in upper limb surgery [28]. How-
a 75% increase in the duration of postoperative analge- ever, it has been suggested that adequate regional
sia with the use of a single 100 lg dose of perineural anaesthesia for the knee joint requires blockade of
dexmedetomidine as an adjuvant to femoral and sciatic both femoral and sciatic nerves [29]. The lack of sci-
nerve blocks [8]. atic nerve blockade in our study may account for the
Most earlier studies utilised empirical single doses discrepancy between the duration of sensory block and
levels of perineural dexmedetomidine ranging from time to first request for rescue analgesia. The shorter

1182 © 2016 The Association of Anaesthetists of Great Britain and Ireland

 13652044, 2016, 10, Downloaded from https://associationofanaesthetists-publications.onlinelibrary.wiley.com/doi/10.1111/anae.13603, Wiley Online Library on [06/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Abdulatif et al. | Dose–response of dexmedetomidine and femoral nerve block Anaesthesia 2016, 71, 1177–1185

duration of postoperative analgesia could also be sedation [43]. In our study, the 75 lg dose of
related to the differential block of sensory nerve fibres dexmedetomidine was associated with the longest
and the earlier recovery of touch sensation; perception duration of postoperative analgesia, and with the high-
of surgical pain correlates with recovery of Ab touch est incidence of hypotensive episodes. Use of the 50 lg
fibres [30]. Different recovery profiles for Ab, Ad and dose level in high-risk surgical patients may provide a
C fibres with consistent and reproducible earlier recov- good compromise between extended duration of post-
ery of touch sensation has been objectively reported operative analgesia and haemodynamic side-effects.
with the use of the cutaneous current perception Significant sedation has been reported with the use
threshold method in clinical settings after lidocaine- of perineural dexmedetomidine in awake volunteers [9,
induced spinal [30], epidural [31] and transcutaneous 13], and in patients receiving combined brachial plexus
nerve block [32]. block and general anaesthesia [18]. The sedative effect
Extended duration of sensory block is generally of perineural dexmedetomidine is dose-dependent and
desirable, especially if associated with improved post- peaks at 60–90 min [9]. We did not identify any sig-
operative analgesia. In contrast, prolonged motor block nificant differences in sedation between the four study
may be associated with delayed ambulation and groups. This could be related to the use of compara-
increased risk of falls in patients undergoing lower tively low doses of dexmedetomidine. It could also be
limb surgeries [33]. There is good clinical evidence due to the confounding effects of general anaesthesia,
that the use of lower concentrations of local anaesthet- with peak sedation effects most likely to occur in the
ics [34] or selective adductor canal block [35–37] are intra-operative period.
useful motor-sparing alternatives to conventional Our study has some limitations. First, we used
femoral nerve block. It is possible that the use of pinprick testing to evaluate sensory block. The addi-
dexmedetomidine (with a lower concentration of local tional use of loss to touch sensation and the cutaneous
anaesthetic) in adductor canal block could be associ- current perception threshold method [30–32] could
ated with extended duration of sensory block, while explain the discrepancy between duration of sensory
sparing motor function. This hypothesis needs to be block and time to first request for rescue postoperative
investigated with further clinical research. analgesia. Second, we used general anaesthesia in com-
The intravenous route of administration for bination with femoral nerve block in all patients. We
dexmedetomidine is associated with a significant were therefore not able to monitor the full spectrum
reduction in arterial blood pressure and heart rate of possible sedative effects of perineural dexmedetomi-
[38]. In contrast, the haemodynamic side-effects of dine. The combined use of spinal anaesthesia and
perineural dexmedetomidine in awake patients are femoral nerve block is frequently utilised for knee sur-
minor, and are mostly related to transient bradycar- gery [44–46], but we chose to use general anaesthesia
dia [7, 13, 26]. There was a similar incidence of to eliminate the possible confounding effects of spinal
bradycardia in each of our study groups. However, anaesthesia on femoral nerve block. Third, the insignif-
hypotension was most frequently seen with the 75 lg icant differences in the incidence of bradycardia
dose, and this may be related to systemic absorption. between the control and the perineural dexmedeto-
Dexmedetomidine is well absorbed systemically after midine groups is not in line with previous reports [7],
extravascular injection [39, 40], with linear dose- and could be explained by the fact that our study was
related plasma concentration [41]. not adequately powered to detect statistical differences
Critically ill patients are more vulnerable to in haemodynamic side-effects.
dexmedetomidine-induced haemodynamic conse- In summary, perineural infiltration of 50 lg and
quences [42]. A recent retrospective cohort study iden- 75 lg dexmedetomidine reduces the onset and pro-
tified increasing age and low baseline arterial blood longs the duration of bupivacaine-induced femoral
pressure as the two most important risk factors for nerve block. It also reduces postoperative analgesic
haemodynamic instability in non-cardiac critically ill requirements in patients undergoing arthroscopic knee
patients receiving intravenous dexmedetomidine for surgery. The 25 lg dose level does not modify the

© 2016 The Association of Anaesthetists of Great Britain and Ireland 1183

 13652044, 2016, 10, Downloaded from https://associationofanaesthetists-publications.onlinelibrary.wiley.com/doi/10.1111/anae.13603, Wiley Online Library on [06/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Anaesthesia 2016, 71, 1177–1185 Abdulatif et al. | Dose–response of dexmedetomidine and femoral nerve block

pharmacodynamic profile of bupivacaine-induced adding dexmedetomidine to ropivacaine. Anesthesia and

Analgesia 2012; 115: 958–62.
femoral nerve block. The best analgesic profile is 14. Chen H, Zhang N, Lu X, Chen S. Caution regarding the choice
achieved with the 75 lg dose level, but this dose is of standard deviations to guide sample size calculations in
associated with increased risk of hypotension. clinical trials. Clinical Trials 2013; 10: 522–9.
15. Abdulatif M, Mukhtar A, Obayah G. Pitfalls in reporting sam-
ple size calculation in randomized controlled trials published
Acknowledgements in leading anaesthesia journals: a systematic review. British
Journal of Anaesthesia 2015; 115: 699–707.
This study was registered with the Clinical Trials.gov 16. Bartel AK, Campoy L, Martin-Flores M, et al. Comparison of
(NCT02089932). No external funding or competing bupivacaine and dexmedetomidine femoral and sciatic nerve
interests declared. blocks with bupivacaine and buprenorphine epidural injection
for stifle arthroplasty in dogs. Veterinary Anaesthesia and
Analgesia 2015; 43: 435–43.
References 17. Marhofer D, Kettner SC, Marhofer P, Pils S, Weber M, Zeitlinger
1. Fischer HB, Simanski CJ, Sharp C, et al. A procedure-specific M. Dexmedetomidine as an adjuvant to ropivacaine prolongs
systematic review and consensus recommendations for post- peripheral nerve block: a volunteer study. British Journal of
operative analgesia following total knee arthroplasty. Anaes- Anaesthesia 2013; 110: 438–42.
thesia 2008; 63: 1105–23. 18. Fritsch G, Danninger T, Allerberger K, et al. Dexmedetomidine
2. Murray JM, Derbyshire S, Shields MO. Lower limb blocks. added to ropivacaine extends the duration of interscalene
Anaesthesia 2010; 65 (Suppl. S1): 57–66. brachial plexus blocks for elective shoulder surgery when
3. Kirksey MA, Haskins SC, Cheng J, Liu SS. Local anesthetic compared with ropivacaine alone: a single-center, prospec-
peripheral nerve block adjuvants for prolongation of analge- tive, triple-blind, randomized controlled trial. Regional Anes-
sia: a systematic qualitative review. PLoS ONE 2015; 10: thesia and Pain Medicine 2014; 39: 37–47.
e0137312. 19. Vadhanan P, Tripaty DK, Adinarayanan S. Physiological and
4. Po€pping DM, Elia N, Marret E, Wenk M, Trame r MR. Clonidine pharmacologic aspects of peripheral nerve blocks. Journal of
as an adjuvant to local anesthetics for peripheral nerve and Anaesthesiology Clinical Pharmacology 2015; 31: 384–93.
plexus blocks: a meta-analysis of randomized trials. Anesthe- 20. Hogan Q. Size of human lower thoracic and lumbosacral nerve
siology 2009; 111: 406–15. roots. Anesthesiology 1996; 85: 37–42.
5. Lundblad M, Trifa M, Kaabachi O, et al. Alpha-2 adrenoceptor 21. Eng HC, Ghosh SM, Chin KJ. Practical use of local anesthetics
agonists as adjuncts to peripheral nerve blocks in children: a in regional anesthesia. Current Opinion in Anaesthesiology
meta-analysis. Pediatric Anesthesia 2016; 26: 232–8. 2014; 27: 382–7.
6. Brummett CM, Norat MA, Palmisano JM, Lydic R. Perineural 22. Becker DE, Reed KL. Local anesthetics: review of pharmaco-
administration of dexmedetomidine in combination with bupi- logical considerations. Anesthesia Progress 2012; 59: 90–102.
vacaine enhances sensory and motor blockade in sciatic nerve 23. White P, Lewith G, Prescott P. Should we recruit patients or
block without inducing neurotoxicity in rat. Anesthesiology healthy volunteers for acupuncture studies of chronic pain?
2008; 109: 502–11. Clinical Journal of Pain 2007; 23: 714–9.
7. Abdallah FW, Brull R. Facilitatory effects of perineural 24. Brummett CM, Hong EK, Janda AM, Amodeo FS, Lydic R. Per-
dexmedetomidine on neuraxial and peripheral nerve block: a ineural dexmedetomidine added to ropivacaine for sciatic
systematic review and meta-analysis. British Journal of Anaes- nerve block in rats prolongs the duration of analgesia by
thesia 2013; 110: 915–25. blocking the hyperpolarization-activated cation current. Anes-
8. Helal SM, Eskandr AM, Gaballah KM, Gaarour IS. Effects of per- thesiology 2011; 115: 836–43.
ineural administration of dexmedetomidine in combination 25. €nnqvist PA. Alpha-2 adrenoceptor agonists as adjuncts to
Lo
with bupivacaine in a femoral-sciatic nerve block. Saudi Jour- peripheral nerve blocks in children: is there a mechanism of
nal of Anesthesia 2016; 10: 18–24. action and should we use them? Pediatric Anesthesia 2012;
9. Keplinger M, Marhofer P, Kettner SC, Marhofer D, Kimberger O, 22: 421–4.
Zeitlinger M. A pharmacodynamic evaluation of dexmedeto- 26. Esmaoglu A, Yegenoglu F, Akin A, Turk CY. Dexmedetomidine
midine as an additive drug to ropivacaine for peripheral nerve added to levobupivacaine prolongs axillary brachial plexus
blockade: a randomised, triple-blinded, controlled study in block. Anesthesia and Analgesia 2010; 111: 1548–51.
volunteers. European Journal of Anaesthesiology 2015; 32: 27. Bharti N, Sardana DK, Bala I. The analgesic efficacy of
790–6. dexmedetomidine as an adjunct to local anesthetics in supra-
10. Marhofer P, Brummett CM. Safety and efficiency of dexmedeto- clavicular brachial plexus block: a randomized controlled trial.
midine as adjuvant to local anesthetics. Current Opinion in Anesthesia and Analgesia 2015; 121: 1655–60.
Anaesthesiology 2016; doi:10.1097/ACO.0000000000000364. 28. Russon K, Pickworth T, Harrop-Griffiths W. Upper limb blocks.
11. Taha AM, Abd-Elmaksoud AM. Ropivicaine in ultrasound- Anaesthesia 2010; 65 (Suppl. S1): 48–56.
guided femoral nerve block: what is the minimum effective 29. Wegener JT, van Ooij B, van Dijk CN, Hollmann MW, Preckel B,
anaesthetic concentration (EC90)? Anaesthesia 2014; 69: 678– Stevens MF. Value of single-injection or continuous sciatic
82. nerve block in addition to a continuous femoral nerve block
12. Sessler CN, Gosnell M, Grap MJ, et al. The Richmond Agita- in patients undergoing total knee arthroplasty: a prospective,
tion-Sedation Scale: validity and reliability in adult intensive randomized, controlled trial. Regional Anesthesia and Pain
care patients. American Journal of Respiratory and Critical Medicine 2011; 36: 481–8.
Care Medicine 2002; 166: 1338–44. 30. Liu S, Kopacz DJ, Carpenter RL. Quantitative assessment of dif-
13. Rancourt MP, Albert NT, Co ^te
 M, Le
tourneau DR, Bernard PM. ferential sensory nerve block after lidocaine spinal anesthesia.
Posterior tibial nerve sensory blockade duration prolonged by Anesthesiology 1995; 82: 60–3.

1184 © 2016 The Association of Anaesthetists of Great Britain and Ireland

 13652044, 2016, 10, Downloaded from https://associationofanaesthetists-publications.onlinelibrary.wiley.com/doi/10.1111/anae.13603, Wiley Online Library on [06/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Abdulatif et al. | Dose–response of dexmedetomidine and femoral nerve block Anaesthesia 2016, 71, 1177–1185

31. Sakura S, Sumi M, Yamada Y, Saito Y, Kosaka Y. Quantitative during total intravenous anaesthesia. Anaesthesia 2015; 70:
and selective assessment of sensory block during lumbar 1052–9.
epidural anaesthesia with 1% or 2% lidocaine. British Journal 39. Anttila M, Penttil€a J, Helminen A, Vuorilehto L, Scheinin H.
of Anaesthesia 1998; 81: 718–22. Bioavailability of dexmedetomidine after extravascular doses
32. Sakai T, Tomiyasu S, Yamada H, Ono T, Sumikawa K. Quantita- in healthy subjects. British Journal of Clinical Pharmacology
tive and selective evaluation of differential sensory nerve 2003; 56: 691–3.
block after transdermal lidocaine. Anesthesia and Analgesia 40. Dyck JB, Maze M, Haack C, Vuorilehto L, Shafer SL. The phar-
2004; 98: 248–51. macokinetics and hemodynamic effects of intravenous and
33. Johnson RL, Kopp SL, Hebl JR, Erwin PJ, Mantilla CB. Falls and intramuscular dexmedetomidine hydrochloride in adult human
major orthopaedic surgery with peripheral nerve blockade: a volunteers. Anesthesiology 1993; 78: 813–20.
systematic review and meta-analysis. British Journal of 41. Scheinin H, Jaakola ML, Sjo €vall S, et al. Intramuscular
Anaesthesia 2013; 110: 518–28. dexmedetomidine as premedication for general anesthesia. A
34. Beebe MJ, Allen R, Anderson MB, Swenson JD, Peters CL. Con- comparative multicenter study. Anesthesiology 1993; 78:
tinuous femoral nerve block using 0.125% bupivacaine does 1065–75.
not prevent early ambulation after total knee arthroplasty. Clin- 42. Tan JA, Ho KM. Use of dexmedetomidine as a sedative and
ical Orthopaedics and Related Research 2014; 472: 1394–9. analgesic agent in critically ill adult patients: a meta-analysis.
35. Abdallah FW, Whelan DB, Chan VW, et al. Adductor canal block Intensive Care Medicine 2010; 36: 926–39.
provides non-inferior analgesia and superior quadriceps 43. Ice CJ, Personett HA, Frazee EN, Dierkhising RA, Kashyap R,
strength compared with femoral nerve block in anterior cruci- Oeckler RA. Risk factors for dexmedetomidine-associated
ate ligament reconstruction. Anesthesiology 2016; 124: hemodynamic instability in non-cardiac intensive care unit
1053–64. patients. Anesthesia and Analgesia 2016; 122: 462–9.
36. Westergaard B, Jensen K, Lenz K, et al. A randomised con- 44. Gaudreault F, Drolet P, Fallaha M, Varin F. Modeling the anes-
trolled trial of ultrasound-guided blockade of the saphenous thetic effect of ropivacaine after a femoral nerve block in
nerve and the posterior branch of the obturator nerve for orthopedic patients: a population pharmacokinetic-pharmaco-
postoperative analgesia after day-case knee arthroscopy. dynamic analysis. Anesthesiology 2015; 122: 1010–20.
Anaesthesia 2014; 69: 1337–44. 45. Hanson NA, Allen CJ, Hostetter LS, et al. Continuous ultra-
37. Kwofie MK, Shastri UD, Gadsden JC, et al. The effects of ultra- sound-guided adductor canal block for total knee arthroplasty:
sound-guided adductor canal block versus femoral nerve a randomized, double-blind trial. Anesthesia and Analgesia
block on quadriceps strength and fall risk: a blinded, random- 2014; 118: 1370–7.
ized trial of volunteers. Regional Anesthesia and Pain Medi- 46. Perlas A, Kirkham KR, Billing R, et al. The impact of analgesic
cine 2013; 38: 321–5. modality on early ambulation following total knee arthro-
38. Lee SH, Choi YS, Hong GR, Oh YJ. Echocardiographic evaluation plasty. Regional Anesthesia and Pain Medicine 2013; 38:
of the effects of dexmedetomidine on cardiac function 334–9.

© 2016 The Association of Anaesthetists of Great Britain and Ireland 1185