Anaesthesia - 2021 - Desai - Local Anaesthetic Adjuncts For Peripheral Regional Anaesthesia A Narrative Review

Anaesthesia 2021, 76 (Suppl. 1), 100–109 doi:10.1111/anae.
15245
Review Article
Local anaesthetic adjuncts for peripheral regional

anaesthesia: a narrative review
N. Desai,1,2 K. R. Kirkham3 and E. Albrecht4
1 Consultant, Department of Anaesthesia, Guy’s and St Thomas’ NHS Foundation Trust, London, UK
2 Honorary Senior Clinical Lecturer, King’s College London, London, UK
3 Assistant Professor, Department of Anaesthesia and Pain Management, Toronto Western Hospital, University of
Toronto, ON, Canada
4 Program Director, Department of Anaesthesia, University Hospital of Lausanne and University of Lausanne, Lausanne,
Switzerland
Summary
Moderate-to-severe postoperative pain persists for longer than the duration of single-shot peripheral nerve
blocks and hence continues to be a problem even with the routine use of regional anaesthesia techniques. The
administration of local anaesthetic adjuncts, defined as the concomitant intravenous or perineural injection of
one or more pharmacological agents, is an attractive and technically simple strategy to potentially extend the
benefits of peripheral nerve blockade beyond the conventional maximum of 8–14 hours. Historical local
anaesthetic adjuncts include perineural adrenaline that has been demonstrated to increase the mean duration
of analgesia by as little as just over 1 hour. Of the novel local anaesthetic adjuncts, dexmedetomidine and
dexamethasone have best demonstrated the capacity to considerably improve the duration of blocks.
Perineural dexmedetomidine and dexamethasone increase the mean duration of analgesia by up to 6 hour and
8 hour, respectively, when combined with long-acting local anaesthetics. The evidence for the safety of these
local anaesthetic adjuncts continues to accumulate, although the findings of a neurotoxic effect with perineural
dexmedetomidine during in-vitro studies are conflicting. Neither perineural dexmedetomidine nor
dexamethasone fulfils all the criteria of the ideal local anaesthetic adjunct. Dexmedetomidine is limited by side-
effects such as bradycardia, hypotension and sedation, and dexamethasone slightly increases glycaemia. In
view of the concerns related to localised nerve and muscle injury and the lack of consistent evidence for the
superiority of the perineural vs. systemic route of administration, we recommend the off-label use of systemic
dexamethasone as a local anaesthetic adjunct in a dose of 0.1–0.2 mg.kg 1 for all patients undergoing surgery
associated with significant postoperative pain.
.................................................................................................................................................................
Correspondence to: E. Albrecht
Email: eric.albrecht@chuv.ch
Accepted: 29 July 2020
Keywords: local anaesthetic adjuncts; local anaesthetics; nerve block
Twitter: @DrKyleKirkham; @DrEAlbrecht
Introduction postoperative ambulation; the development of chronic

Moderate-to-severe postoperative pain is common and pain; and increased mortality. The administration of opioids
remains an unresolved problem [1]. It has been associated to control postoperative pain has been related to adverse
with decreased patient satisfaction; an increased incidence effects such as constipation, nausea and vomiting, pruritus
of pulmonary and cardiac complications; delayed and secondary hyperalgesia [2]. Compared with opioid-
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Desai et al. | Local anaesthetic adjuncts Anaesthesia 2021, 76 (Suppl. 1), 100–109
based analgesia alone, the administration of local peripheral nerve blockade. In this review, we will consider
anaesthetics in peripheral nerve blockade has long been how the different potential local anaesthetic adjuncts
associated with better pain relief [3]. Despite this compare with the ideal theoretical model, and explore the
improvement in analgesia, one drawback of single-shot importance of the various routes of administration.
peripheral nerve blockade is its limited duration of action.
The offset of peripheral nerve blockade can also be Historical local anaesthetic adjuncts
characterised by the occurrence of rebound pain, that is Adrenaline
severe surgical pain due to unopposed nociceptive inputs, Adrenaline is one of the oldest perineural adjuncts and is
on resolution of the block [4]. This phenomenon of commonly administered with local anaesthetics in peripheral
rebound pain can result in unanticipated overnight sleep nerve blockade. It is often co-administered as a marker of
disturbance, increased consumption of opioids, and intravascular injection. If simultaneously administered for
difficulties in compliance with enhanced recovery and prolongation of peripheral nerve blockade, its mechanism of
physiotherapy protocols. Given these outcomes, strategies action after perineural administration is likely to be, at least in
have been explored to extend the benefits of peripheral part, due to a1-adrenoreceptor mediated vasoconstriction
nerve blockade beyond the traditional maximum of 8–14 h (Fig. 1). In a meta-analysis of six randomised controlled trials
[5, 6]. (RCT) using short-acting (lidocaine), intermediate-acting
Continuous peripheral nerve blockade is defined as the (mepivacaine) and long-acting (ropivacaine) local
percutaneous insertion of a catheter adjacent to a anaesthetics, Tschopp et al. demonstrated that perineural
peripheral nerve, plexus or fascial plane, followed by the adrenaline increased the mean duration of analgesia by
administration of local anaesthetic through the catheter. 66 min. Two of the included trials also indicated its capacity
This modality has been associated with decreased rebound to prolong the motor component of the block [15].
pain [7] and improved postoperative analgesia [8] relative Adrenaline has been found to delay the systemic absorption
to single-shot peripheral nerve blockade. Due to catheter of local anaesthetic with the resultant possibility of
migration, obstruction or shearing, fluid leakage and decreasing the risk of local anaesthetic systemic toxicity [16].
infusion pump malfunction, the rate of secondary block Concerns have been raised in regard to an increased
failure has been reported to be as high as 20–50% [9, 10]. susceptibility to neurotoxicity secondary to the decrease in
Other complications include: inaccurate placement of the blood flow to the peripheral nerve when perineural
catheter tip; knotting; catheter-related mechanical nerve adrenaline is administered. In patients with acquired
irritation; inflammation at the insertion site; bacterial peripheral neuropathy, the American Society of Regional
colonisation; and local anaesthetic systemic toxicity [11]. Anesthesia recommends that the anaesthetic technique be
Further, in contrast to the single-shot femoral nerve block, modified with the elimination, or reduction in the
continuous femoral or psoas compartment blocks have concentration, of adrenaline [17]. In the experience of the
been related to an increased risk of falls [12]. In the opinion authors, adverse effects, such as significant tachycardia and
of the authors, the main limitation restraining the hypertension, are rare.
disseminated use of continuous catheter techniques has
been the resource and service provision needed to Buprenorphine
accommodate the increase in costs, training and follow-up. Buprenorphine is a MOP (l) partial opioid receptor agonist
Liposomal bupivacaine is a simpler alternative which does and KOP (j) opioid receptor agonist. Its mechanism of
not require this increase in resource and service provision. It action after perineural administration is likely to be due to
refers to the encapsulation of bupivacaine into lipid bilayer concentration-dependent blockade of voltage-gated
spherical vesicles, a strategy intended to prolong its release sodium channels, inhibiting the generation of action
into the area of targeted injection. Unfortunately, meta- potentials [18], and interaction with MOP opioid receptors
analyses to date have not supported the additional benefit on the axons of unmyelinated C fibres [19].
of these prolonged release formulations for operative site In a meta-analysis of 11 RCTs, Schnabel et al. evaluated
infiltration or single-shot peripheral nerve blockade [13, 14]. perineural buprenorphine in mainly brachial plexus
The use of local anaesthetic adjuncts, defined as the blockade, but also femoral and sciatic nerve blocks [20].
simultaneous administration of one or more They demonstrated that its co-administration increased the
pharmacological agents around a peripheral nerve, plexus or mean duration of analgesia and motor block by 518 min
fascial plane or systemically by i.v. injection, is an alternative and 13 min, respectively. No clinically significant
strategy to influence the characteristics of the resulting differences in the time to onset of sensory or motor block
© 2021 Association of Anaesthetists 101

Anaesthesia 2021, 76 (Suppl. 1), 100–109 Desai et al. | Local anaesthetic adjuncts
VASOCONSTRICTION (d)
Epinephrine
Dexamethasone
(a) A
(c) C
(b)
Figure 1 Mechanisms of action of local anaesthetic adjuncts on the cell membrane of neurones and the blood vessels. (a)
Dexamethasone stimulates glucocorticoid receptors, increasing the expression of inhibitory potassium channels and
decreasing the excitability of neurones. (b) Clonidine and dexmedetomidine inhibit the hyperpolarisation-activated nucleotide-
gated channels, maintaining the neurone at a more negative potential and hence hyperpolarised state. (c) Buprenorphine
inhibits voltage-gated sodium channels, preventing the generation of action potentials, and interacts with MOP (l) receptors. (d)
Magnesium results in the hyperpolarisation of the neurone secondary to the interaction between its positive divalent charge and
the neuronal membrane.
were found. The influence of the analgesic effect provided Clonidine

by buprenorphine extended up to 48 h postoperatively, Clonidine is a non-selective imidazoline derivative and
with the mean pain score at 24–48 h decreased by 1.25 an a2-adrenoreceptor agonist. Its mechanism of action
points on a scale of 0–10. The results of this systematic after perineural administration is unlikely to be due to
review were limited by funnel plot asymmetry and thus the activity at a2-adrenoreceptors as they are not present
potential for publication bias or small studies effects. on the axons of peripheral nerves. Instead, clonidine is
Adverse effects of buprenorphine included postoperative thought to block the hyperpolarisation-activated
nausea and vomiting and pruritus, although none of the nucleotide-gated channels that are responsible for the
patients in the included trials received prophylaxis against hyperpolarisation-activated cation currents. In the
these complications. With regard to neurotoxicity, an refractory phase of the action potential, these channels
in-vitro study examining buprenorphine at high facilitate restoration of the neurone resting potential
concentration when co-administered with ropivacaine and resumption of functional activity. Clonidine is
found no such increased effect relative to ropivacaine alone hence able to maintain the Ad and C neurones in a
on dorsal root ganglia isolated from rats [21]. In a follow-up hyperpolarised state, thereby inhibiting the generation
in-vivo study, sciatic nerve blocks with bupivacaine and of action potentials. It could further work by inducing
buprenorphine in rats did not result in histopathological or localised vasoconstriction mediated through its less
neurobehavioural concerns [22]. selective stimulation of a1-adrenoreceptors.

In a meta-analysis of 20 RCTs, Popping et al. evaluated also femoral nerve and thoracic paravertebral blocks [27].
perineural clonidine at a dose range of 30–300 lg in mainly They demonstrated that its co-administration increased the
brachial plexus blockade, but also ankle, cervical plexus, duration of analgesia, sensory block and motor block by
femoral, iliohypogastric, ilio-inguinal and sciatic nerve 125 min, 107 min and 90 min, respectively. No clinically
blocks [23]. They demonstrated that its co-administration significant differences in the time to onset of sensory or
increased the mean duration of analgesia, sensory block motor block were found. Neither the need for rescue
and motor block by 123 min, 74 min and 141 min, analgesia nor the occurrence of postoperative nausea and
respectively, irrespective of whether short-acting (lidocaine vomiting were influenced by the administration of perineural
or prilocaine), intermediate-acting (mepivacaine) or long- magnesium. With regard to neurotoxicity, the evidence for
acting (bupivacaine or ropivacaine) local anaesthetics were intrathecal magnesium is inconsistent [28, 29] and the safety
administered. No clinically significant differences in the time of perineural magnesium has not been investigated.
to onset of sensory or motor block were found. Adverse
effects of clonidine included bradycardia, hypotension, Miscellaneous
fainting and sedation, favouring its use in patients who are at Hyaluronidase is an enzyme that degrades hyaluronic acid,
low rather than high anaesthetic risk and increasing the a glycosaminoglycan which connects to proteoglycans in
potential need for peri-operative monitoring. No evidence the orbital connective tissue. Its administration in orbital
for a dose-response relationship was found, probably blocks can enhance the spread of local anaesthetic and is
because most patients received the same dose of 150 µg. considered to provide improved akinesia and analgesia. In
The optimal dose of perineural clonidine, at which a meta-analysis of seven trials, however, Ruschen et al.
beneficial effects are maximised and harmful effects are showed that it did not decrease intra-operative pain scores,
minimised, has therefore not yet been determined. With although patient and surgical satisfaction were increased
regard to neurotoxicity, an in-vitro study examining [30].
clonidine at high concentration when co-administered with Sodium bicarbonate results in the alkalinisation of the
ropivacaine revealed an increased effect relative to injected local anaesthetic solution, increasing its pH closer
ropivacaine alone on dorsal root ganglia isolated from rats to the pKa of the local anaesthetic and favouring its
[21]. It is challenging, however, to translate benchside conversion to the non-ionised form. This transition improves
findings to the clinical bedside because of a potential the penetration of local anaesthetic through the neuronal
overestimation of neurotoxicity in the setting of in-vitro membrane to reach its intracellular site of action. The co-
studies, for many reasons. First, isolated neurones sustain administration of sodium bicarbonate is thought to reduce
mechanical injury in the process, increasing their the time to onset of the block, but the evidence to
susceptibility to a second insult [17]. Second, the lack of corroborate this in respect of perineural administration is
normal diffusion and vascular absorption mechanisms conflicting [31, 32].
increases the drug concentration at the neuronal In view of the inconsistent or limited evidence to
membrane. Third, neuronal cell bodies are more vulnerable support their efficacy or the potential for significant adverse
to injury relative to distal axons. In a follow-up in-vivo study, effects or neurotoxicity, the perineural use of midazolam,
sciatic nerve blocks with bupivacaine and clonidine in rats fentanyl, morphine, tramadol, ketamine and neostigmine is
did not result in histopathological or neurobehavioural not advocated (Table 1).
changes [22].'
Novel local anaesthetic adjuncts
Magnesium Dexmedetomidine, an a2-adrenoreceptor agonist and non-
Magnesium is an N-methyl-D-aspartate (NMDA) receptor selective imidazoline derivative similar to clonidine, and
antagonist that has been demonstrated to increase the dexamethasone, a potent long-acting glucocorticoid with
excitation threshold more in myelinated Ab than minimal mineralocorticoid activity, have been extensively
unmyelinated C fibres [24, 25]. Its mechanism of action after investigated as novel local anaesthetic adjuncts.
perineural administration is likely to be due to the effects of
its positive divalent charge on the neuronal membrane Dexmedetomidine
potential and its molecular physiological function as a Compared with the a2:a1 activity ratio of 220:1 for
calcium antagonist [26]. In a meta-analysis of seven RCTs, clonidine, dexmedetomidine exhibits a ratio of 1620:1 [33].
Mengzhu et al. evaluated perineural magnesium with mainly Dexmedetomidine is, hence, eight times more selective for
bupivacaine in predominantly brachial plexus blockade, but a2-adrenoreceptors than clonidine. Its mechanism of action

Table 1 Summary of evidence for local anaesthetic dexmedetomidine, at which the duration of the sensory
adjuncts that have demonstrated limited benefits and/or block is maximised and the haemodynamic adverse effects
increased neurotoxicity and side-effects. are minimised, has been determined to be 50–60 lg. Helal
Adjunct Evidence et al. reported similar efficacy and side-effects of perineural
Midazolam Limited demonstrated perineural effectiveness dexmedetomidine following femoral and sciatic nerve
Evidence of in-vitro and in-vivo neurotoxicity blocks as those subsequent to brachial plexus blockade
No increase in neurological symptoms
[36]. With respect to neurotoxicity, the evidence is
after intrathecal injection in humans
inconsistent. An in-vivo study evaluating dexmedetomidine
Fentanyl Conflicting findings for perineural
effectiveness overall at high doses revealed that it was neuroprotective with
Possible efficacy if administered with decreased perineural inflammation in rats when it was co-
bupivacaine administered with bupivacaine [37]. This effect may be
Side-effects reported include hypercapnia,
bradycardia and sedation secondary to the inhibition of activated nuclear factor NF-jB
Morphine Conflicting findings for perineural [38], and thus the downstream transcription of pro-
effectiveness inflammatory cytokines, and the modulation of mast cell
No clear evidence of superiority over degranulation [39]. In a more recent in-vivo study, however,
systemic administration
dexmedetomidine at high doses increased neurotoxicity in
Tramadol Conflicting findings for perineural
rats when co-administered with ropivacaine [40].
effectiveness
No clear evidence of superiority over
systemic administration Dexamethasone
Ketamine Lack of demonstrated perineural effectiveness Dexamethasone has a mechanism of action after perineural
Evidence of in-vitro and in-vivo neurotoxicity administration that is likely to be due to stimulation of
Side-effects reported include drowsiness,
hallucinations and nausea glucocorticoid receptors located on the neuronal
Neostigmine Lack of demonstrated perineural effectiveness membrane, increasing the expression of inhibitory
Evidence of in-vitro and in-vivo neurotoxicity potassium channels and hence decreasing the excitability of
Significant side-effect profile, including unmyelinated C fibres. It could further work by inducing
nausea and vomiting
localised vasoconstriction or through systemic anti-
inflammatory processes following vascular absorption.
after perineural administration is likely to be similar to that of Numerous meta-analyses have evaluated perineural
clonidine, although unlike clonidine it is not thought to dexamethasone in mainly brachial plexus blockade, but also
mediate localised vasoconstriction through a1- dental, peribulbar, sciatic nerve and transversus abdominis
adrenoreceptor stimulation. plane blocks [41, 42]. In a meta-analysis of 29 trials, Albrecht
In a meta-analysis of 34 RCTs, Vorobeichik et al. et al. demonstrated that its co-administration increased the
evaluated perineural dexmedetomidine in only brachial mean duration of analgesia by 233 min and 488 min if
plexus blockade [34]. They demonstrated that its co- injected with short- (lidocaine or prilocaine), medium-
administration increased the mean duration of analgesia, (mepivacaine) or long-acting (bupivacaine, levobupivacaine
sensory block and motor block by 264 min, 228 min and or ropivacaine) local anaesthetics, respectively [41]. Further, in
192 min, respectively. One of the included trials indicated this systematic review, perineural dexamethasone prolonged
that dexmedetomidine can produce a differential the mean duration of motor block by 150 min and 286 min
sensorimotor effect, extending sensory block without when injected with short or intermediate-acting and long-
prolonging motor block [35]. This finding may reflect a acting local anaesthetics, respectively. No clinically significant
possible greater inhibitory effect on Ad and C nerve fibres differences in the time to onset of sensory or motor block were
relative to motor neurones. Perineural dexmedetomidine found. Dexamethasone decreased pain score at rest and on
decreased the time to onset of sensory block from 20 min to movement at 8–12 h and 24 h, and reduced cumulative
11 min and reduced the time to onset of motor block from morphine consumption at 24 h. Despite its findings, the
21 min to 13 min [34]. Further, it lowered the cumulative results of this meta-analysis were limited by funnel plot
morphine consumption at 24 h and was associated with asymmetry and thus the potential for publication bias or small
improved patient satisfaction. Adverse effects of studies effects. In brachial plexus blockade, perineural
dexmedetomidine included bradycardia, hypotension and dexamethasone has a ceiling effect on the mean duration of
sedation. No evidence for a dose-response relationship was analgesia at a dose of 4 mg with short- or intermediate-acting
found, but the optimal dose of perineural and long-acting local anaesthetics [43, 44].

Dexamethasone can induce an increase in the mean duration of analgesia, sensory block and motor block
postoperative blood glucose concentration subsequent to by 205 min, 188 min and 162 min, respectively [51]. No
either perineural or i.v. administration. After perineural clinically significant differences in the time to onset of
administration of dexamethasone, a RCT demonstrated the sensory or motor block were found. These findings may be a
mean increase in postoperative blood glucose reflection of the more pronounced inhibitory effect
1
concentration to be 0.2 mmol.l [45]. Following i.v. dexmedetomidine has on neuronal action potentials
administration of dexamethasone, a RCT found the relative to clonidine. Perineural dexmedetomidine, on the
maximum increase in postoperative blood glucose other hand, was associated with an increased incidence of
1
concentration at 4 h to be 1.7 mmol.l [46]. The theoretical adverse effects such as bradycardia and sedation relative to
concerns of delayed wound healing and wound or systemic clonidine. Albrecht et al. demonstrated that both perineural
infection were not demonstrated in a systematic review [47]. dexmedetomidine and dexamethasone, compared with
With respect to neurotoxicity, an in-vitro study control, increased the mean duration of analgesia by
examining dexamethasone demonstrated that it 346 min and 482 min, respectively [52]. Perineural
attenuated the cytotoxic effect of bupivacaine on mouse dexamethasone, compared with dexmedetomidine,
neuroblastoma cells [48]. In another in-vitro study, increased the mean duration of analgesia by 148 min,
dexamethasone at high concentration when co- without prolongation of sensory or motor block. No
administered with ropivacaine did not have an incremental clinically significant differences in the time to onset of
neurotoxic effect relative to ropivacaine alone on dorsal sensory or motor block were found. Moreover, perineural
root ganglia isolated from rats [21]. Further, during a follow- dexamethasone showed a reduced risk of adverse effects
up in-vivo study, sciatic nerve blocks performed with such as hypotension and sedation relative to
bupivacaine and dexamethasone in rats did not result in dexmedetomidine. The characteristics of perineural
histopathological or neurobehavioural changes [22]. In dexmedetomidine and dexamethasone are compared with
human trials to date, perineural dexamethasone has not the theoretical ideal local anaesthetic adjunct in Table 3.
been associated with neurological complications [41, 42],
and no neurological sequelae were reported in a series of Comparison of perineural and
over 2000 intrathecal injections of dexamethasone for post- intravenous routes of local anaesthetic
traumatic visual disturbance [49]. Nevertheless, lack of adjunct administration
evidence for harm is not evidence of absence. Given the low Given the efficacy of local anaesthetic adjuncts when
incidence of nerve injury subsequent to regional administered perineurally, the focus of recent research has
anaesthesia techniques, it has previously been estimated shifted to determine whether the beneficial effects can be
that a sample size of approximately 16,000 patients would maintained with systemic use. If equally effective, this route
be required to show a doubling of the baseline of systemic administration would obviate the concerns of
complication rate of 0.4% [50]. localised nerve or muscle injury related to perineural use.
In the absence of peripheral nerve blockade,
Choice of local anaesthetic adjunct for dexamethasone, administered intravenously at a dose of
perineural administration 0.1–0.2 mg.kg 1
, decreased postoperative pain and opioid
For all local anaesthetic adjuncts, the advantages of consumption [53]. If used as an adjunct to peripheral nerve
extending the duration of analgesia and sensory block must blockade, previous meta-analyses indicate that perineural
be considered and weighed against the disadvantages of dexamethasone increased the mean duration of analgesia
the lengthened motor block duration and the risks of by approximately 180 min, decreased the morphine-
adverse effects and neurotoxicity. equivalent opioid consumption at 24 h by a mean of 7 mg
Several meta-analyses of supraclavicular brachial and reduced the postoperative pain score at 12 h and 24 h
plexus blockade with long-acting local anaesthetics compared with i.v. administration [42, 54, 55]. Further
(bupivacaine, levobupivacaine or ropivacaine) have subgroup analysis in one systematic review demonstrated
suggested the presence of superior block characteristics that the increase in duration of analgesia was statistically
with dexmedetomidine vs. clonidine and dexamethasone significant with bupivacaine but not ropivacaine [54]. In a
vs. dexmedetomidine in terms of indices of block subsequent meta-analysis, however, in contrast to the
characteristics when administered perineurally (Table 2) preceding three, perineural dexamethasone was not found
[51, 52]. El-Boghdadly et al. demonstrated that perineural to provide any incremental gains with regard to the duration
dexmedetomidine, compared with clonidine, increased the of analgesia, possibly due to the utilisation of a more

Table 2 Comparison of the effect of local anaesthetic adjuncts administered perineurally on indices of block characteristics and
incidence of side-effects. All data have been extracted from meta-analyses and their included trials.
Cumulative
postoperative
Pain opioid
scores consumption
Onset of Onset of at less at 24
Duration of sensory Duration of motor Duration than or h; morphine
analgesia; block; sensory block; of motor Block equal equivalents
min min block; min min block; min failure to 24 h in mg Side-effects
Historical local anaesthetic adjuncts

Adrenaline +66 ND Increased/ ND Increased/ ND Not studied Not studied Hypertension
[15] ND ND Tachycardia
Buprenorphine +518 ND Increased/ −0.3 +13 Not Decreased Not studied PONV (RR 5)
[20] ND studied Pruritus (RR 6)
Clonidine [23] +123 −2 +74 ND +141 ND Decreased/ Not studied Bradycardia
ND (OR 3.1)
Arterial
hypotension
(OR 3.6)
Orthostatic
hypotension
(OR 2.3)
Sedation
(OR 5.1)
Magnesium +125 ND +107 −1 +90 ND Decreased Decreased ND
[27]
Novel local anaesthetic adjuncts
Dexmedetomidine +264 −9 +228 to 346 −8 +192 ND Decreased −10 Bradycardia
[34, 52] (OR 7.4)
Sedation
(OR 11.8)
Dexamethasone +233 to 488 −1 +233 to 488 −1 +286 ND Decreased −19 Increase in
[41] mean blood
glucose
concentration
by 0.2 mmol l−1
ND, no difference; PONV, postoperative nausea and vomiting; RR, risk ratio; OR, odds ratio.
conservative methodology in statistical analysis [56]. Since dexamethasone [58]. Similar to the variability shown in
the publication of these systematic reviews, two RCTs have studies investigating dexamethasone, trials investigating
furthered our understanding of dexamethasone as a the relative effects of i.v. and perineural clonidine or
potential local anaesthetic adjunct. In the first trial, the dexmedetomidine are inconsistent in their findings
addition of perineural or i.v. dexamethasone to ropivacaine [35, 59–62].
for ulnar nerve block in healthy volunteers did not increase
the duration of sensory block [57]. In view of the absence of Off-label administration of local
a surgical stimulus, it is probable that these results do not anaesthetic adjuncts
reflect clinical practice. Should the mechanism of action be In order to safeguard their effectiveness, quality and safety,
predominantly systemic following vascular absorption, the medications are licensed by regulatory authorities for
anti-inflammatory effects of dexamethasone would have approved indications, doses, routes of administration and
had no target in the design of this trial and the lack of effect specific patient populations. Examples of such regulatory
is thus to be expected. In the second trial, injection of authorities include the European Medicines Agency, Food
perineural or i.v. dexamethasone with ropivacaine for and Drug Administration and the Medicines and Healthcare
interscalene brachial plexus blockade in shoulder products Regulatory Agency.
arthroscopy revealed a clinically insignificant increase in Despite the guidance provided by these regulatory
the duration of analgesia of 45 min in favour of i.v. authorities, it is common clinical practice to prescribe drugs

Table 3 Comparison of the characteristics of an ideal local Conclusion

anaesthetic adjunct with perineural dexmedetomidine and
In conclusion, local anaesthetic adjuncts, either
dexamethasone.
administered intravenously or perineurally, are a promising
Characteristics of and technically simple alternative to other strategies for
an ideal local
anaesthetic adjunct Dexmedetomidine Dexamethasone extending the beneficial effects of peripheral nerve
blockade. None of the potential medications investigated to
Available as a + +
preservative-free date fulfil all the criteria of the ideal local anaesthetic
preparation adjunct, but dexmedetomidine and dexamethasone
Chemically + +* demonstrate the most supporting evidence. In the opinion
compatible with of the authors, however, dexmedetomidine is more limited
local anaesthetics
by its adverse side-effect profile than dexamethasone. It
Plausible + +
mechanism of
remains unclear whether the perineural or systemic route of
action administration is superior. In view of this, and in
Effective for all nerve + + acknowledgement of the concerns regarding the
blocks neurotoxic effects of all potential local anaesthetic adjuncts,
No chrondrotoxic, ? + we recommend the off-label use of systemic
myotoxic and 1
dexamethasone at a dose of 0.1 −0.2 mg.kg for all
neurotoxic effects
patients undergoing surgery where moderate or severe
Evidence of dose- +
response postoperative pain is expected.
relationship
Increase in the + + Acknowledgements
duration of The authors thank F. Elwen, Core Trainee in Anaesthetics at
analgesia
Guy’s and St Thomas’ NHS Foundation Trust, for her
Increase in the + +
duration of sensory drawing of the figures. EA has received grants from the
block Swiss Academy for Anaesthesia Research, Lausanne,
No prolongation of Switzerland (50,000 CHF; no grant number attributed), B.
motor block Braun Medical AG (56,100 CHF; no grant number
No significant + attributed), and from the Swiss National Science Foundation
systemic side-
(353,408 CHF; grant number 32003B_169974/1) in order to
effects
support his clinical research. EA has further received
+, yes; ?, unclear; , no.
honoraria from B. Braun Medical AG and Sintetica Ltd UK.
*Dexamethasone is not compatible with ropivacaine in-vitro.
No other competing interests declared.
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Anaesthesia 2021, 76 (Suppl. 1), 100–109 doi:10.1111/anae.

Local anaesthetic adjuncts for peripheral regional

Introduction postoperative ambulation; the development of chronic

100 © 2021 Association of Anaesthetists

© 2021 Association of Anaesthetists 101

were found. The inﬂuence of the analgesic effect provided Clonidine

102 © 2021 Association of Anaesthetists

© 2021 Association of Anaesthetists 103

104 © 2021 Association of Anaesthetists

© 2021 Association of Anaesthetists 105

Historical local anaesthetic adjuncts

106 © 2021 Association of Anaesthetists

Table 3 Comparison of the characteristics of an ideal local Conclusion

© 2021 Association of Anaesthetists 107

108 © 2021 Association of Anaesthetists

© 2021 Association of Anaesthetists 109

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