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SP38.1 Update on adjuvants for paediatric PNBs
  1. Per-Arne Lönnqvist


Karolinska Institute, Stockholm, Sweden

This is an excerpt from the publication: Suresh S, Ecoffey C, Bosenberg A, Lonnqvist PA, de Oliveira GS Jr, de Leon Casasola O, de Andrés J, Ivani G. The European Society of Regional Anaesthesia and Pain Therapy/American Society of Regional Anesthesia and Pain Medicine Recommendations on Local Anesthetics and Adjuvants Dosage in Pediatric Regional Anesthesia. Reg Anesth Pain Med. 2018 Feb;43(2):211–216. doi: 10.1097/AAP.0000000000000702. PMID: 29319604.

Adjuvants in Pediatric regional Anesthesia

Per-Arne Lönnqvist

Initial word of caution/Disclaimer With the exception of clonidine and preservative free morphine none of the other adjuvant agents mentioned in this practice advisory guideline are registered for spinal/epidural administration. None of the agents are registered for injection close to peripheral nerve structures. Thus, the decision to use the drugs mentioned below as adjuvants to pediatric regional anesthesia will be governed by the individual practitioner´s decision, departmental policy and the existing medicolegal situation.

Rational for using adjuvants

Even long-acting local anesthetics (racemic bupivacaine, levo-bupivacaine and ropivacaine) have a limited duration of action (typically 4–12 h of duration) balanced against the time period of more intense postoperative pain associated with moderate or major surgery (24–72 h). Prolongation of the block effect in order to better match pain duration can be accomplished by the use of catheter techniques that will allow repeated bolus administration or continuous infusion of local anesthetics.1 However, the majority of pediatric surgical interventions do not merit the use of these more complicated and resource demanding options for postoperative analgesia. Thus, a popular alternative to achieve prolongation of a single injection nerve block is to use adjuvant drugs that are mixed with the local anesthetics and thereby increase the duration of the nerve block.2,3

Some of the advantages associated with the use of adjuvants drugs:

a. Will increase block duration in such a way that it may be possible to perform the surgical procedure before the block starts to wear off (e.g. neonatal spinal anesthesia)

b. Reduced general anesthetic requirement

c. Prolongation of the analgesic duration of the block

d. Allow for a smooth emergence from anesthesia and a calm recover room stay

e. Reduce the incidence of emergence delirium and shivering

f. In the context of ambulatory surgery provide a comfortable early postoperative period that will allow early discharge from the hospital and a pain free transfer back home

Fundamental requirements of adjuvant drugs Not only does there need to be published evidence for an enhanced effect compared to control (plain local anesthetics), a candidate adjuvant has to fulfill some further important requirements:

a. Preferably meta-analysis data should verify the beneficial effect of the adjuvant in order to recommend routine use outside clinical trials

b. There should be sufficient insight into the mechanism of action of the adjuvant

c. The side effect profile should be tolerable in comparison with the use of plain local anesthetics

d. The adjuvant must be available as a preservative-free preparation

e. Overall safety issues must be acceptable

List of published adjuvants used in association with neuraxial blocks in children include:

a. Preservative-free morphine

b. Synthetic opioids (fentanyl, sufentanil, buprenorphine, diamorphine)

c. Alpha-2 adrenoceptor agonists (clonidine, dexmedetomidine)

d. Racemic ketamine and S-ketamine

e. Corticosteroids (dexamethasone)

f. Midazolam

g. Neostigminie

h. Magnesium

Some of these adjuvants (midazolam, neostigmine, buprenorphine) have been tested, mostly off label and without proper pre-clinical trials, and their side effects outweigh the benefits limiting clinical use.4 Others (dexamethasone, fentanyl) have little or no added benefit over intravenously administered route of the same agent.

Definition of clinically relevant prolongation of analgesic effect

No consensus currently exists regarding the definition of what may be considered a clinically relevant prolongation of postoperative analgesia achieved by the use of adjuvant drugs in the context of pediatric regional anesthesia. However, it has been suggested that the postoperative duration of the analgesic effect of the block should be increased more than 20–50 % compared to control (plain local anesthetics)2 and that the absolute time increase should be at least two hours compared to control to be considered of value for the pediatric patient.2

Toxicity aspects Potential risks of nerve root and spinal cord neurotoxicity is of paramount importance in the context of neuraxial blocks in children. Laboratory in vitro studies do point to potential neurotoxicity associated with certain adjuncts but clinical toxicity has to date not been reported in the literature (but, under-reporting is likely). However, in parallel with the potential risks of cerebral neurotoxicity following early exposure to general anesthetics, the more frequently used adjuvants used in pediatric regional anesthesia have undergone animal testing to investigate whether spinal administrations of these drugs may cause apoptosis of spinal cord neurons.5–8 These reports show that local anesthetics (levo-bupivacaine), preservative-free morphine and clonidine do not increase apoptosis in neonatal mice5,7,8 whereas ketamine was found to cause increased apoptosis in this setting.6 As a result of these studies Walker & Yaksh have strongly suggested that new adjunct alternatives should undergo similar testing before being applied in the clinical setting, especially in neonates and small infants.9 Against this background only clonidine and preservative-free morphine may currently be advocated for use in neonates and infants.10

Dexmedetomidine has recently been shown to have positive effects as an adjuvant both for caudal and peripheral nerve blocks in children.11,12 This drug does also seem to be associated with acceptable safety features13 and may, thus, be a new interesting alternative in this setting.

Data regarding the use of adjuvants and peripheral nerve blocks in children are scarce but it may be reasonable to expect that drugs that are safe from a central nerve block perspective will also be safe to use when performing peripheral nerve blocks. Again it is important to note that any adjuvant that is used in association with peripheral nerve blockade must have a defined mechanism of action since peripheral nerves lack the expression of many of the receptors that are responsible for the adjunct’s effect in the central nerve block setting.14

Neuraxial blocks The issues regarding neuroaxial and the use of adjuvant drugs have recently been highlighted in a recent review.3

Intrathecal/Spinal blockade: Clonidine and the synthetic opioids fentanyl and sufentanil have been shown to prolong the duration of surgical blockade in babies.15–17 Whether these agents will prolong postoperative analgesia in a clinically relevant way is still unknown. Intrathecal administration of morphine has mainly been performed in association with major spine surgery in older children (e.g. scoliosis surgery)18 but is associated with substantially more prolonged postoperative analgesia. However, in this context morphine is commonly injected as a single agent and not mixed with local anesthetics.

Caudal blockade: This represents the most frequently performed pediatric nerve block worldwide19–21 and the vast majority of studies regarding adjuvants have been performed in this setting.

Racemic ketamine and S-ketamine Meta-analysis data show that ketamine does produce a useful adjuvant effect when co-delivered with LA 22,23 and ketamine appears as more effective to prolong postoperative analgesia when compared to clonidine.24 It must be emphasized that racemic ketamine can only be used if the preparation is preservative-free (preservatives are present is some commercially available ketamine formulations) and that ketamine is not recommended in neonates and infants due to the possible potential for enhanced neuronal apoptosis in the spinal cord. S-ketamine can also be used25 and since this enantiomeric version of ketamine only exists as a preservative-free solution, this may be a preferred option if available.

Clonidine and dexmedetomidine Meta-analysis data clearly support a beneficial effect of clonidine as an adjuvant in the caudal block setting.26–28 The analgesic effect of clonidine is comparable to that of preservative-free morphine but is associated with shorter effect duration.29 A number of individual studies, including a recent meta-analysis (11), has shown dexmedetomidine to prolong postoperative analgesia when used as a caudal block adjunct. The effect size of dexmedetomidine appears very similar to that of clonidine despite the considerable difference in elimination half-life between these two alpha-2 adrenoceptor agonists.30

Preservative-free morphine Meta-analysis data for caudal morphine is lacking but a number of reports do attest to the efficacy of this adjunct in the setting of caudal blockade. Morphine does also have the advantage of a clearly defined dose-response, showing that increasing the dose to > 50 mcg kg-1 will not enhance the effect but only increases the risk for respiratory depression.31 Due to the hydrophilic nature of morphine this agent can successfully be used for surgery outside the area usually covered by a caudal block. Thus, caudal administration of morphine has been shown to produce prolonged analgesia even following sternotomy in pediatric cardiac surgery32 (please cf epidural blockade below). However, the use of caudal morphine is associated with an increase of side effects (e.g. pruritis, PONV, paralytic ileus).33–35 Furthermore, caudal administration of morphine is associated with a risk of delayed respiratory depression that necessitates adequate postoperative monitoring for at least 12–24 hours following administration.36

Synthetic opioids Although these agents are popular as adjuvants in the context of adult epidural analgesia there is currently a lack of evidence that synthetic opioids produce any relevant effect when used as adjuvants to caudal blocks in children.33 Fentanyl does not potentiate the effect of either bupivacaine or ropivacaine in the context of caudal blockade.37

Corticosteroids Only two studies so far has reported a beneficial effect of dexamethasone as a caudal adjuvant.38,39 Despite the fact that caudal/epidural steroid injections in adults appear to be associated with reasonable safety there is a lack of toxicity data regarding the intraspinal deposition of corticosteroids in growing individuals. Furthermore, no mechanism has so far been identified that can explain how adjuvant use of corticosteroids in the context of central or peripheral nerve blocks is supposed to work. In addition, recent adult data show that intravenous administration of dexamethasone produces identical prolongation of block duration as deposition of dexamethasone together with local anesthetics close to the target nerve structures40, which is also supported by pediatric data.41,42 Thus, at this point adjuvant use of corticosteroids as adjuncts to local anesthetics in children cannot be recommended outside clinical trials.

Epidural blockade: Data relating to the effect of adjuvants in association with epidural analgesia in children is very sparse. As with caudal block, epidural co-administration of morphine will enhance the effect of epidural local anesthetics.35 An advantage of epidural morphine is that it does not require administration at the spinal segments associated with the surgical intervention and, thus, may be an attractive alternative when the tip of the epidural catheter is not located at the optimal spinal level.32 Epidural morphine is rarely administered as a continuous infusion but instead as repeated bolus injections.35

Regarding clonidine, dose-response data are available that show that the addition of clonidine to a low concentration of ropivacaine will enhance the effect of the local anesthetic infusion.43 In contrast, the adjunct use of synthetic opioids as adjunct to pediatric epidural analgesia does not appear to be associated with any clinically significant effect.44,45

Peripheral nerve blocks Alpha-2 adrenoceptor agonists. Peripheral nerves lack the expression of alpha-2 adrenoceptors but clonidine and dexmedetomidine act by interference with the repolarization process through interactions with the I h current (14). Furthermore, adult meta-analyses have verified a beneficial effect of adjuvant use of alpha-2 adrenoceptors in the context of peripheral nerve blocks.46,47

In the pediatric context a large single center study showed that adjuvant use of clonidine is associated with a prolongation of peripheral block duration in the order of 20–50 %.48 Recently a meta-analysis with full access to all raw data of the included randomized controlled trials showed a definite advantage in favor of the use of adjuvant alpha-2 adrenoceptors,49 a beneficial effect that remained even after the exclusion of the one RCT that investigated the use of dexmedetomidine.50

Data for other adjuvants in the setting of peripheral nerve blockade is largely lacking.

Combinations of adjuncts At certain centers the combination of adjuvants is popular. The combined use of clonidine and opioids lead to a reduction of opioid induced side effects (e.g. pruritis and PONV) with no enhancement of postoperative analgesia.51 A prospective RCT using a combination of clonidine and fentanyl administered together with local anesthetics for paravertebral blockade in the setting of inguinal hernia repair produced significantly better postoperative analgesia compared to a ilioinguinal/iliohypogastric nerve block using plain local anesthetics52 or systemic multimodal analgesia.53 Finally, Hager et al have shown that the caudal co-administration of S-ketamine and clonidine, without the administration of local anesthetics (!), results in approximately 24 hours of postoperative analgesia.54

At this time point combinations of adjuvants lack supportive data and toxicology data are lacking. Thus, the combination of adjuvant drugs cannot be recommended outside clinical trials.

Conclusions 1. Neuroaxial blocks

a. Caudal blocks: Meta-analysis data show that adjuvant use of clonidine is associated with improved postoperative analgesia compared to plain local anesthetics. Preservative-free ketamine is also effective in this setting but animal toxicity data suggest that ketamine should be avoided in newborns and infants due to a potential risk of increased neuronal apoptosis within the spinal cord. (Evidence A1).

b. Epidural blocks: Adjuvant use of preservative-free morphine and clonidine improve the quality of postoperative analgesia (Evidence A3)

c. Intrathecal blocks: Adjuvant use of preservative-free morphine, synthetic opioids and clonidine improve the quality and duration of intrathecal blocks (Evidence A3)

2. Peripheral nerve blocks

a. Meta-analysis data show that adjuvant use of preservative-free clonidine is associated with improved postoperative analgesia compare to plain local anesthetics (Evidence A3).

b. No other adjuvants have been shown to improve postoperative analgesia in the context of peripheral nerve blocks in children.

3. New potential adjuvant drugs should undergo proper toxicologic testing before being used in the human setting and new candidate drugs should first be properly investigated in clinical trials before being generally used in routine patient care.


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