Pediatric Anesthesia ISSN 1155-5645
REVIEW ARTICLE
Adjuncts should always be used in pediatric regional anesthesia € nnqvist1,2 Per-Arne Lo 1 Paediatric Anaesthesia & Intensive Care, Section of Anaesthesiology & Intensive Care, Department of Physiology & Pharmacology, Karolinska Institutet, Stockholm, Sweden 2 Paediatric Anaesthesia, Inetsive Care & ECMO Services, Astrid Lindgrens Children’s Hospital/Karolinska University Hospital-Solna, Stockholm, Sweden
Keywords adjuncts; child; clonidine; infant; ketamine; morphine; regional anesthesia Correspondence €nnqvist, Paediatric Anaesthesia Per-Arne Lo & Intensive Care, ALB/Karolinska-Solna, SE 171 76 Stockholm, Sweden Email: [email protected]
Summary A number of different adjuncts to local anesthetics can be used to prolong and optimize postoperative pain relief following regional anesthesia in children. The present text provides a slightly opinionated but evidence-based argument in favor of this practice.
Section Editor: Neil Morton Accepted 15 August 2014 doi:10.1111/pan.12526
Introduction The pain associated with various types of surgical interventions in children often extends well into the postoperative period. For major surgery, this can easily be solved by the use of continuous catheter techniques. However, many surgical interventions are relatively minor in nature (e.g., inguinal hernia repair, orchidopexy, circumcision, umbilical hernia) and do not motivate the use of continuous catheters. Despite using long-acting local anesthetics, the block duration of single-injection techniques is frequently insufficient to cover the major part of the first 24 postoperative hours, which often is the most painful part of the postoperative period. Thus, if the duration of a single-injection block can be adequately prolonged by modest and safe means, it is reasonable to view the resulting prolongation of highquality pain relief as a clinically relevant improvement for the patient. The use of adjunct drugs in combination with longacting local anesthetics may not only prolong block duration in a desirable fashion but can also improve block quality and avoid potential side effects of longacting local anesthetics, for example, unwanted motor 100
weakness, by being able to use LALA concentrations that by itself do produce an unreliable nerve block (1,2). Challenging orthodoxy If the use of adjuncts to long-acting local anesthetics does not result in such prolongation of block duration that it will cover the entire period of more intense postoperative pain (at least 24–48 h), then it is not worth doing due to the possible risks and side effects of such practice, for example, drug-related side effects or potential drug mixing errors. This orthodoxy is still not infrequently voiced by Professor Peter Davies and other ‘conventionalists’. However, to refrain from optimizing, the potential of your nerve-blocking technique appears illogical to other anesthesiologists. Thus, the above orthodoxy has been challenged by many, who believe that prolongation of block duration by >50% is certainly clinically relevant for improving child comfort during the often distressing early postoperative period. Thus, the counter argument is that every hour of excellent pediatric postoperative pain relief counts whether it can be achieved easily and without any serious side effects or complications. © 2014 John Wiley & Sons Ltd Pediatric Anesthesia 25 (2015) 100–106
€nnqvist P.-A. Lo
Adjuncts should always be used in pediatric regional anesthesia
In Europe, the ‘nonuse’ orthodoxy has in effect been seriously challenged for many years now. Already in 2002, Sanders reported that a majority (59%) of UKbased anesthesiologists regularly used adjuncts when performing caudal blocks (3). Further reports supporting the frequent use of adjuncts in pediatric regional anesthesia have followed since (4). The rest of this communication will be devoted to the knowledge base behind the use of adjuncts in pediatric regional anesthesia. Thereafter, the reader will be able to make an informed choice whether to start to (or continue to) challenge the ‘nonuse’ orthodoxy or to stay (or convert to?) being a ‘conventionalist’.
When doing preclinical or clinical studies, a change in effect of the magnitude of 20–25 percent is other accepted as being ‘relevant’. In the context of postoperative analgesia, we might be stricter before we say that a new treatment option is clinically relevant. However, a change that is ≥ 50% compared with established practice would by many be accepted as being clearly relevant and desirable in a clinical context. So, what adjunct drugs live up to this quite high degree of efficacy? The most powerful adjunct with regard to prolonging the duration of analgesia following a single-injection caudal block is preservative-free morphine that often will provide up to 24 h of good-quality postoperative analgesia (8,9). This may be a very useful adjunct under special circumstances, but is associated with certain disturbing side effects (e.g., postoperative nausea and vomiting, pruritus, paralytic ileus) (10) as well as the need for prolonged supervision of the patient due to the risk of delayed respiratory depression (11). These limitations associated with caudal/epidural morphine have come to restrict its widespread use. Structured reviews or meta-analysis regarding the use of either ketamine (12) or clonidine (13) as adjuncts to caudal blockade in children shows a prolongation of postoperative analgesia of approximately 50% compared with plain long-acting local anesthetics. The alpha-2 agonist dexmedetomidine appears as a new promising alternative in this context (14) and has also been shown to prolong the effect of peripheral nerve blockade by 60% in adult volunteers (15). However, no meta-analysis is currently available and basic safety issues need further study. A large number of other adjunct drugs have been used in association with caudal blocks in children, but all these alternatives are associated with either lack of efficacy (e.g., synthetic opioids), unacceptable side effects (e.g., excessive PONV rates associated with buprenorphine and neostigmine) or lack of any reasonable toxicity testing when administered in close proximity to the neuroaxis (e.g., midazolam). At present, these drugs can therefore not be recommended for use outside clinical trials (16).
What represents clinically relevant prolongation of a single-injection nerve block? This obviously represents a key issue in this context. Ideally, the duration of the pain relief caused by the block should match the relevant pain duration of the procedure, which in many cases continues for 2–3 days postoperatively. Attempts to achieve this magnitude of block prolongation have been made by encapsulating long-acting local anesthetics into, for example, liposomes or microspheres that theoretically will allow for ‘slow release’ of long-acting local anesthetics for extended periods. This has so far not been crowned with any major success, although some formulations have recently become commercially available within the United States (e.g., ExparelR) (5). Another very interesting and promising new development to achieve prolonged nerve blockade by single injections is the use of site 1 sodium channel blockers that bind to another part of the sodium channel than long-acting local anesthetics (please see below, ‘mechanism of action’). These compounds belong to a group of naturally occurring toxins; of which, tetrodotoxin may be the most widely known representative. When used as adjuncts to long-acting local anesthetics, they are capable of producing very substantial block prolongation (6). Neosaxitoxin, derived from blooming red algae found in the waters outside Chile, appears as a very promising candidate for eventual clinical use. When compared to bupivacaine alone, it has been shown to provide extended pain relief, reduced duration of hospital stay, and more rapid recovery in adults undergoing laparoscopic cholecystectomy (7). Pediatric clinical trials investigating the usefulness and side effects of neosaxitoxin are currently underway, spearheaded by Berde and Cravero (personal communication). However, until this eventually becomes commercially available, we will have to rely on less powerful adjuncts. © 2014 John Wiley & Sons Ltd Pediatric Anesthesia 25 (2015) 100–106
Mechanisms of action To gain general acceptance, each adjunct should have an identified mechanism of action. Concerning neuroaxial nerve blocks, all commonly used adjunct drugs work through various receptors and associated mechanisms in the dorsal horn of the spinal cord. Thus, the most commonly used adjuncts morphine, ketamine, and clonidine exert their effect by binding to l-, NMDA-, and alpha-2 receptors, respectively. 101
Adjuncts should always be used in pediatric regional anesthesia
€nnqvist P.-A. Lo
As drug-related receptors are virtually nonexistent on peripheral nerves, it is not surprising that attempts at using various adjunct drugs in the setting of peripheral nerve blockade have been largely unsuccessful. However, two drug classes do have clarified mechanisms of action. Site 1 sodium channel blockers, for example, neosaxitoxin, bind to a different site of the sodium channel as compared to local anesthetics. Based on this fact, it is not difficult to imagine that co-administration of LALA and neosaxitoxin may be capable of producing a potent synergistic effect (7). As indicated above, peripheral nerves lack the expression of alpha-2 receptors and, thus, the beneficial effect of adjunct use of clonidine and dexmedetomidine cannot be explained by alpha-2 receptor stimulation (17). However, laboratory research has clearly shown that these drugs are capable of causing quite powerful interference with the hyperpolarization-activated cation current (Ih current), which is necessary for the return of normal conductivity following a depolarization of the nerve (17). Thus, alpha-2 agonists will interfere with nerve conductivity in a somewhat similar way as LALA and could potentially also produce sensory selectivity as this effect appears to be more pronounced in C-fibers (pain) than in A-alpha fibers (motor). One drug class that recently has attracted interest as an adjunct to LALA in adults is co-administration of steroids, for example, dexamethasone (18). The effects may seem quite impressive, especially if mixed with other adjuncts as a cocktail (e.g., mixed with epinephrine and clonidine) (19). However, one should in the authors mind remain skeptical to the use of steroids as adjuncts as there is no clearly defined mechanism of action and it is not clear whether perineural administration is better than systemic administration (18,20). Furthermore, no pediatric studies have so far been published showing adequate efficacy and safety. Based on the above, adjunct use of steroids in pediatric regional anesthesia should only be allowed within clinical trials.
tive-free morphine for caudal or epidural blockade, the picture is quite clear as the dose of morphine used is too small to allow for any major long-acting systemic component of analgesia associated with its use (8). However, regarding the adjunct use of synthetic highly lipophilic opioids (e.g., fentanyl and sufentanil), the situation is completely different since soon after the introduction of this concept in the late 1980s; it could be shown that the there was no appreciable difference in dose and analgesia if the synthetic opioid was administered epidurally or intravenously. Not surprisingly, the evidence base for the adjunct use of synthetic opioids as adjuncts to neuroaxial blocks in children is weak, not to say nonexistent (22). Maybe the most unclear picture is associated with the adjunct use of ketamine as the doses commonly used are not too different compared with those used for intravenous pain relief or even induction of anesthesia (23). The most valid argument for a predominantly local effect in the dorsal horn of the spinal cord is that the duration of postoperative analgesia achieved with adjunct use of S-ketamine substantially outlasts the effect of a similar intramuscular dose (24). Although supported by a strong evidence base, the primarily spinal effect of adjunct clonidine in the setting of caudal blockade has been questioned by a Danish study, reporting similar analgesic effects whether clonidine was given caudally or intravenously (25). However, extensive animal studies performed by the Eisenach group have been able to show that the main effect of epidural clonidine in fact is caused by spinal mechanisms (26). The fact that sensory and motor block duration is significantly longer following intrathecal vs intravenous clonidine in the setting of pediatric spinal anesthesia lends further support for a mainly spinal effect of clonidine in this context (27). Even if the main effect is produced by binding to alpha-2 receptors in the dorsal horn, some supplementary effect will be added by systemic uptake with subsequent action on the locus coeruleus and the peri-aqueductal gray area.
Local vs systemic effects of adjuncts
Neuroaxial blocks
Even with regard to the use of only long-acting local anesthetics, it can be difficult to properly determine how much of the analgesic effect is due to the localized effect on the nerve structures and how much is due to absorption of the local anesthetics with subsequent systemic analgesic actions. As an example, quite potent analgesia can be achieved by intravenous administration of local anesthetics in the context of spine surgery (21). The same issue is highly relevant when it comes to the use of adjuncts. Concerning the adjunct use of preserva-
As the duration of intrathecal blockade is very short in infants and children, even when using LALA (e.g., bupivacaine) (28), a prolongation of the duration of action caused by adjuncts would be very useful. Due to the relatively limited clinical use of intrathecal blockade in children, few studies have been published concerning adjuncts in this specific setting, but evidence for clinically relevant prolongation of spinal blockade does exist for epinephrine, morphine, fentanyl, and clonidine (29).
102
© 2014 John Wiley & Sons Ltd Pediatric Anesthesia 25 (2015) 100–106
€nnqvist P.-A. Lo
Adjuncts should always be used in pediatric regional anesthesia
As stated previously, an abundant literature supports the adjunct use of morphine, ketamine, and clonidine when performing caudal blockade. The efficacy of adjuncts in the setting of continuous epidural analgesia in children has received relatively little proper scientific attention. As has been alluded to above (please see, Local vs systemic effects of adjuncts), the adjunct use of synthetic opioids does not enhance the anesthetic effect compared with long-acting local anesthetics alone (30). The use of morphine can be useful when the epidural catheter tip is not optimally positioned in relation to the surgical incision as the analgesic effect of epidural morphine is not dependent of the actual point of deposition within the spinal canal (9). However, the use of epidural morphine is associated with the potential risk for respiratory depression and is also frequently associated with minor but distressing side effects, for example, pruritus, nausea/vomiting, and postoperative paralytic ileus (10,11). With regard to clonidine, a dose-finding study by De Negri et al. (31) did find that infusion rates of ≥ 0.1 mcgkg 1h 1 enhanced the quality of postoperative analgesia compared with ropivacaine alone. Concerning adjunct use of ketamine in the setting of pediatric epidural analgesia, there is currently a lack of proper scientific data.
LA (36). Although this rarely does result in any major problems, significant nerve injury can still occur. In this setting, the adjunct use of clonidine may again be advantageous as Eisennach et al. in animal studies have shown a protective effect of clonidine if administered at the site of injury (37,38).
Peripheral blocks The support for use of adjuncts in the setting of peripheral nerve blocks in children is sparse and mainly limited to the use of clonidine. Adult metaanalyses have found clonidine to prolong the quality and duration of peripheral nerve blocks (17). Relatively small and under-powered pediatric studies have not been able to confirm the effect seen in adults, showing at best only weak trends in favor of adjunct clonidine (32–34). However, a large review of the regional anesthesia database at Philadelphia children’s hospital reports quite compelling data, showing that the adjunct use of clonidine prolongs block duration by 20–50% depending on the type of block performed (35). However, this effect was only seen when dilute concentrations of long-acting local anesthetics were used (bupivacaine 0125%, ropivacaine 0.2%). No data are currently available for dexmedetomidine in this context, but adult volunteer data show that the duration of an ulnar nerve block is prolonged by 60% by adjunct administration of dexmedetomidine (15). Despite the use of ultrasound guidance, unintentional puncture of the perineurium happens rather frequently and may even be associated with intraneural injection of © 2014 John Wiley & Sons Ltd Pediatric Anesthesia 25 (2015) 100–106
Wound installation and infiltration In common with many peripheral nerve blocks, the classic use of epinephrine as an adjunct will prolong the duration of analgesia even by local installation following inguinal surgery in children (39). The mechanism of action most likely being an increase in time that the long-acting local anesthetics is present at the site of action due to local vasoconstriction caused by the alpha-1 effect of epinephrine, thereby slowing systemic uptake of long-acting local anesthetics. In the context of tonsillectomy, local infiltration of ropivacaine together with clonidine in the tonsillar fossa prior to the start of surgery has been reported not only to increase the duration of immediate postoperative analgesia but also to reduce the pain on swallowing during the first five postoperative days (40). The mechanism behind this potentially ‘preemptive’ effect of clonidine when used for infiltration is obscure, and the effect reported by Gianonni et al. (40) has to date not been verified by any similar study. Local infiltration of ketamine has also been reported to be beneficial in children undergoing adeno-tonsillectomy (41). Side effects and safety The potential side effects and complications of adjunct use of morphine have already been mentioned above. Interestingly, the side effects of epidurally administered opioids can be ameliorated by the concomitant administration of adjunct clonidine (42). In this context, it may be added that systemic co-administration of clonidine will not potentiate the respiratory depression caused by morphine alone (43). Based on the published literature, the use of ketamine as adjunct to regional anesthesia appears to be associated with few and mild side effects. As there will be systemic uptake of the locally deposited ketamine, it should be remembered that the use of systemic ketamine has also been associated with the development of postoperative apnea in premature babies (44). The various effects that can/will result from the inevitable systemic uptake of adjunct clonidine (45) can mostly be viewed as positive spin-off effects rather than unwanted side effects (46). Clinically 103
€nnqvist P.-A. Lo
Adjuncts should always be used in pediatric regional anesthesia
Table 1 Suggestions on how to use adjuncts in daily clinical practice when performing pediatric regional anesthesia. All adjuncts must be preservative-free Type of block
Recommended adjuncts
Supporting references
Spinal block in expremature babies, neonates and infants Caudal blocks in ex-premature babies, neonates and infants
Clonidine 1 mcgkg 1 Clonidine 1 mcgkg 1 (Morphine 33–50 mcgkg 1, rarely indicated) S-ketamine 0.5 mcgkg 1 Clonidine 1–2 mcgkg 1 Clonidine >0.1 mcgkg 1h 1 Morphine 33–50 mcgkg 1, Intermittent injections 1–3 times daily Clonidine 1–2 mcgkg 1 Clonidine >0.1 mcgkg 1h 1
(28,61) (8,9,13,60,61)
Caudal blocks for children >1 years of age Continuous epidural analgesia with adequate segmental tip position Continuous epidural analgesia with suboptimal segmental tip position Peripheral nerve blocks, single injection Peripheral nerve blocks, continuous infusion
relevant reductions in heart rate and/or blood pressure are rare and easily treated (46). Prolongation of postoperative sedation after adjunct use of clonidine has not been specifically studied in children, but pediatric premedication even with high-dose clonidine (7–8 mcgkg 1) does not prolong postoperative sedation (47). Only one relevant case report exists linking the use of adjunct clonidine to postoperative apnea following awake caudal blockade in an ex-premature baby (48). However, any drug that will affect cerebral neurons may induce postoperative apnea in this specific patient population, and it should be remembered that the use of plain long-acting local anesthetics in this context is associated with altered EEG patterns during the time coinciding with maximum plasma concentrations of long-acting local anesthetics (49). Thus, even in this published case, it is very difficult to determine whether clonidine really was the causative agent. In general, clonidine can be viewed as a very safe alternative as accidental 100-fold overdosage in the setting of caudal anesthesia only resulted in the need for PICU observation (endotracheal intubation/mechanical ventilation was not needed) and was not associated with any signs of local toxicity (50). Potential effects on apoptosis in the spinal cord of very young individuals Although the best retrospective human registry studies have failed to identify any long-term effects of exposure to general anesthesia in early life (51,52), there are abundant animal data, including nonhuman primates (53– 55), which show increased cerebral apoptosis and later negative cognitive and behavioral consequences following exposure to anesthetics during the brain growth spurt period (56). However, the systemic co-administration of alpha-2 agonists in this context has been reported 104
(12,13,23) (31) (8,9) (35) (extrapolated from 31)
to reduce or ameliorate the neurotoxic effects of other anesthetic compounds (57,58). As the spinal cord forms part of the central nervous system, it appears likely that a similar apoptotic effect may be seen also in the spinal cord if exposed to anesthesia-related drugs during infancy. The possible apoptotic effect of spinal administration of anesthesia-related drugs has been investigated in a series of elegant rodent studies by Walker et al. (59– 62). In summary, these studies show that long-acting local anesthetics alone (levo-bupivacaine), clonidine, and preservative-free morphine are associated with a large safety margin between clinically effective dose and the dose associated with any toxic (apoptotic) effects (60–62). In sharp contrast, apoptosis was observed at doses needed to generate an analgesic response of ketamine, resulting in a therapeutic index
REVIEW ARTICLE
Adjuncts should always be used in pediatric regional anesthesia € nnqvist1,2 Per-Arne Lo 1 Paediatric Anaesthesia & Intensive Care, Section of Anaesthesiology & Intensive Care, Department of Physiology & Pharmacology, Karolinska Institutet, Stockholm, Sweden 2 Paediatric Anaesthesia, Inetsive Care & ECMO Services, Astrid Lindgrens Children’s Hospital/Karolinska University Hospital-Solna, Stockholm, Sweden
Keywords adjuncts; child; clonidine; infant; ketamine; morphine; regional anesthesia Correspondence €nnqvist, Paediatric Anaesthesia Per-Arne Lo & Intensive Care, ALB/Karolinska-Solna, SE 171 76 Stockholm, Sweden Email: [email protected]
Summary A number of different adjuncts to local anesthetics can be used to prolong and optimize postoperative pain relief following regional anesthesia in children. The present text provides a slightly opinionated but evidence-based argument in favor of this practice.
Section Editor: Neil Morton Accepted 15 August 2014 doi:10.1111/pan.12526
Introduction The pain associated with various types of surgical interventions in children often extends well into the postoperative period. For major surgery, this can easily be solved by the use of continuous catheter techniques. However, many surgical interventions are relatively minor in nature (e.g., inguinal hernia repair, orchidopexy, circumcision, umbilical hernia) and do not motivate the use of continuous catheters. Despite using long-acting local anesthetics, the block duration of single-injection techniques is frequently insufficient to cover the major part of the first 24 postoperative hours, which often is the most painful part of the postoperative period. Thus, if the duration of a single-injection block can be adequately prolonged by modest and safe means, it is reasonable to view the resulting prolongation of highquality pain relief as a clinically relevant improvement for the patient. The use of adjunct drugs in combination with longacting local anesthetics may not only prolong block duration in a desirable fashion but can also improve block quality and avoid potential side effects of longacting local anesthetics, for example, unwanted motor 100
weakness, by being able to use LALA concentrations that by itself do produce an unreliable nerve block (1,2). Challenging orthodoxy If the use of adjuncts to long-acting local anesthetics does not result in such prolongation of block duration that it will cover the entire period of more intense postoperative pain (at least 24–48 h), then it is not worth doing due to the possible risks and side effects of such practice, for example, drug-related side effects or potential drug mixing errors. This orthodoxy is still not infrequently voiced by Professor Peter Davies and other ‘conventionalists’. However, to refrain from optimizing, the potential of your nerve-blocking technique appears illogical to other anesthesiologists. Thus, the above orthodoxy has been challenged by many, who believe that prolongation of block duration by >50% is certainly clinically relevant for improving child comfort during the often distressing early postoperative period. Thus, the counter argument is that every hour of excellent pediatric postoperative pain relief counts whether it can be achieved easily and without any serious side effects or complications. © 2014 John Wiley & Sons Ltd Pediatric Anesthesia 25 (2015) 100–106
€nnqvist P.-A. Lo
Adjuncts should always be used in pediatric regional anesthesia
In Europe, the ‘nonuse’ orthodoxy has in effect been seriously challenged for many years now. Already in 2002, Sanders reported that a majority (59%) of UKbased anesthesiologists regularly used adjuncts when performing caudal blocks (3). Further reports supporting the frequent use of adjuncts in pediatric regional anesthesia have followed since (4). The rest of this communication will be devoted to the knowledge base behind the use of adjuncts in pediatric regional anesthesia. Thereafter, the reader will be able to make an informed choice whether to start to (or continue to) challenge the ‘nonuse’ orthodoxy or to stay (or convert to?) being a ‘conventionalist’.
When doing preclinical or clinical studies, a change in effect of the magnitude of 20–25 percent is other accepted as being ‘relevant’. In the context of postoperative analgesia, we might be stricter before we say that a new treatment option is clinically relevant. However, a change that is ≥ 50% compared with established practice would by many be accepted as being clearly relevant and desirable in a clinical context. So, what adjunct drugs live up to this quite high degree of efficacy? The most powerful adjunct with regard to prolonging the duration of analgesia following a single-injection caudal block is preservative-free morphine that often will provide up to 24 h of good-quality postoperative analgesia (8,9). This may be a very useful adjunct under special circumstances, but is associated with certain disturbing side effects (e.g., postoperative nausea and vomiting, pruritus, paralytic ileus) (10) as well as the need for prolonged supervision of the patient due to the risk of delayed respiratory depression (11). These limitations associated with caudal/epidural morphine have come to restrict its widespread use. Structured reviews or meta-analysis regarding the use of either ketamine (12) or clonidine (13) as adjuncts to caudal blockade in children shows a prolongation of postoperative analgesia of approximately 50% compared with plain long-acting local anesthetics. The alpha-2 agonist dexmedetomidine appears as a new promising alternative in this context (14) and has also been shown to prolong the effect of peripheral nerve blockade by 60% in adult volunteers (15). However, no meta-analysis is currently available and basic safety issues need further study. A large number of other adjunct drugs have been used in association with caudal blocks in children, but all these alternatives are associated with either lack of efficacy (e.g., synthetic opioids), unacceptable side effects (e.g., excessive PONV rates associated with buprenorphine and neostigmine) or lack of any reasonable toxicity testing when administered in close proximity to the neuroaxis (e.g., midazolam). At present, these drugs can therefore not be recommended for use outside clinical trials (16).
What represents clinically relevant prolongation of a single-injection nerve block? This obviously represents a key issue in this context. Ideally, the duration of the pain relief caused by the block should match the relevant pain duration of the procedure, which in many cases continues for 2–3 days postoperatively. Attempts to achieve this magnitude of block prolongation have been made by encapsulating long-acting local anesthetics into, for example, liposomes or microspheres that theoretically will allow for ‘slow release’ of long-acting local anesthetics for extended periods. This has so far not been crowned with any major success, although some formulations have recently become commercially available within the United States (e.g., ExparelR) (5). Another very interesting and promising new development to achieve prolonged nerve blockade by single injections is the use of site 1 sodium channel blockers that bind to another part of the sodium channel than long-acting local anesthetics (please see below, ‘mechanism of action’). These compounds belong to a group of naturally occurring toxins; of which, tetrodotoxin may be the most widely known representative. When used as adjuncts to long-acting local anesthetics, they are capable of producing very substantial block prolongation (6). Neosaxitoxin, derived from blooming red algae found in the waters outside Chile, appears as a very promising candidate for eventual clinical use. When compared to bupivacaine alone, it has been shown to provide extended pain relief, reduced duration of hospital stay, and more rapid recovery in adults undergoing laparoscopic cholecystectomy (7). Pediatric clinical trials investigating the usefulness and side effects of neosaxitoxin are currently underway, spearheaded by Berde and Cravero (personal communication). However, until this eventually becomes commercially available, we will have to rely on less powerful adjuncts. © 2014 John Wiley & Sons Ltd Pediatric Anesthesia 25 (2015) 100–106
Mechanisms of action To gain general acceptance, each adjunct should have an identified mechanism of action. Concerning neuroaxial nerve blocks, all commonly used adjunct drugs work through various receptors and associated mechanisms in the dorsal horn of the spinal cord. Thus, the most commonly used adjuncts morphine, ketamine, and clonidine exert their effect by binding to l-, NMDA-, and alpha-2 receptors, respectively. 101
Adjuncts should always be used in pediatric regional anesthesia
€nnqvist P.-A. Lo
As drug-related receptors are virtually nonexistent on peripheral nerves, it is not surprising that attempts at using various adjunct drugs in the setting of peripheral nerve blockade have been largely unsuccessful. However, two drug classes do have clarified mechanisms of action. Site 1 sodium channel blockers, for example, neosaxitoxin, bind to a different site of the sodium channel as compared to local anesthetics. Based on this fact, it is not difficult to imagine that co-administration of LALA and neosaxitoxin may be capable of producing a potent synergistic effect (7). As indicated above, peripheral nerves lack the expression of alpha-2 receptors and, thus, the beneficial effect of adjunct use of clonidine and dexmedetomidine cannot be explained by alpha-2 receptor stimulation (17). However, laboratory research has clearly shown that these drugs are capable of causing quite powerful interference with the hyperpolarization-activated cation current (Ih current), which is necessary for the return of normal conductivity following a depolarization of the nerve (17). Thus, alpha-2 agonists will interfere with nerve conductivity in a somewhat similar way as LALA and could potentially also produce sensory selectivity as this effect appears to be more pronounced in C-fibers (pain) than in A-alpha fibers (motor). One drug class that recently has attracted interest as an adjunct to LALA in adults is co-administration of steroids, for example, dexamethasone (18). The effects may seem quite impressive, especially if mixed with other adjuncts as a cocktail (e.g., mixed with epinephrine and clonidine) (19). However, one should in the authors mind remain skeptical to the use of steroids as adjuncts as there is no clearly defined mechanism of action and it is not clear whether perineural administration is better than systemic administration (18,20). Furthermore, no pediatric studies have so far been published showing adequate efficacy and safety. Based on the above, adjunct use of steroids in pediatric regional anesthesia should only be allowed within clinical trials.
tive-free morphine for caudal or epidural blockade, the picture is quite clear as the dose of morphine used is too small to allow for any major long-acting systemic component of analgesia associated with its use (8). However, regarding the adjunct use of synthetic highly lipophilic opioids (e.g., fentanyl and sufentanil), the situation is completely different since soon after the introduction of this concept in the late 1980s; it could be shown that the there was no appreciable difference in dose and analgesia if the synthetic opioid was administered epidurally or intravenously. Not surprisingly, the evidence base for the adjunct use of synthetic opioids as adjuncts to neuroaxial blocks in children is weak, not to say nonexistent (22). Maybe the most unclear picture is associated with the adjunct use of ketamine as the doses commonly used are not too different compared with those used for intravenous pain relief or even induction of anesthesia (23). The most valid argument for a predominantly local effect in the dorsal horn of the spinal cord is that the duration of postoperative analgesia achieved with adjunct use of S-ketamine substantially outlasts the effect of a similar intramuscular dose (24). Although supported by a strong evidence base, the primarily spinal effect of adjunct clonidine in the setting of caudal blockade has been questioned by a Danish study, reporting similar analgesic effects whether clonidine was given caudally or intravenously (25). However, extensive animal studies performed by the Eisenach group have been able to show that the main effect of epidural clonidine in fact is caused by spinal mechanisms (26). The fact that sensory and motor block duration is significantly longer following intrathecal vs intravenous clonidine in the setting of pediatric spinal anesthesia lends further support for a mainly spinal effect of clonidine in this context (27). Even if the main effect is produced by binding to alpha-2 receptors in the dorsal horn, some supplementary effect will be added by systemic uptake with subsequent action on the locus coeruleus and the peri-aqueductal gray area.
Local vs systemic effects of adjuncts
Neuroaxial blocks
Even with regard to the use of only long-acting local anesthetics, it can be difficult to properly determine how much of the analgesic effect is due to the localized effect on the nerve structures and how much is due to absorption of the local anesthetics with subsequent systemic analgesic actions. As an example, quite potent analgesia can be achieved by intravenous administration of local anesthetics in the context of spine surgery (21). The same issue is highly relevant when it comes to the use of adjuncts. Concerning the adjunct use of preserva-
As the duration of intrathecal blockade is very short in infants and children, even when using LALA (e.g., bupivacaine) (28), a prolongation of the duration of action caused by adjuncts would be very useful. Due to the relatively limited clinical use of intrathecal blockade in children, few studies have been published concerning adjuncts in this specific setting, but evidence for clinically relevant prolongation of spinal blockade does exist for epinephrine, morphine, fentanyl, and clonidine (29).
102
© 2014 John Wiley & Sons Ltd Pediatric Anesthesia 25 (2015) 100–106
€nnqvist P.-A. Lo
Adjuncts should always be used in pediatric regional anesthesia
As stated previously, an abundant literature supports the adjunct use of morphine, ketamine, and clonidine when performing caudal blockade. The efficacy of adjuncts in the setting of continuous epidural analgesia in children has received relatively little proper scientific attention. As has been alluded to above (please see, Local vs systemic effects of adjuncts), the adjunct use of synthetic opioids does not enhance the anesthetic effect compared with long-acting local anesthetics alone (30). The use of morphine can be useful when the epidural catheter tip is not optimally positioned in relation to the surgical incision as the analgesic effect of epidural morphine is not dependent of the actual point of deposition within the spinal canal (9). However, the use of epidural morphine is associated with the potential risk for respiratory depression and is also frequently associated with minor but distressing side effects, for example, pruritus, nausea/vomiting, and postoperative paralytic ileus (10,11). With regard to clonidine, a dose-finding study by De Negri et al. (31) did find that infusion rates of ≥ 0.1 mcgkg 1h 1 enhanced the quality of postoperative analgesia compared with ropivacaine alone. Concerning adjunct use of ketamine in the setting of pediatric epidural analgesia, there is currently a lack of proper scientific data.
LA (36). Although this rarely does result in any major problems, significant nerve injury can still occur. In this setting, the adjunct use of clonidine may again be advantageous as Eisennach et al. in animal studies have shown a protective effect of clonidine if administered at the site of injury (37,38).
Peripheral blocks The support for use of adjuncts in the setting of peripheral nerve blocks in children is sparse and mainly limited to the use of clonidine. Adult metaanalyses have found clonidine to prolong the quality and duration of peripheral nerve blocks (17). Relatively small and under-powered pediatric studies have not been able to confirm the effect seen in adults, showing at best only weak trends in favor of adjunct clonidine (32–34). However, a large review of the regional anesthesia database at Philadelphia children’s hospital reports quite compelling data, showing that the adjunct use of clonidine prolongs block duration by 20–50% depending on the type of block performed (35). However, this effect was only seen when dilute concentrations of long-acting local anesthetics were used (bupivacaine 0125%, ropivacaine 0.2%). No data are currently available for dexmedetomidine in this context, but adult volunteer data show that the duration of an ulnar nerve block is prolonged by 60% by adjunct administration of dexmedetomidine (15). Despite the use of ultrasound guidance, unintentional puncture of the perineurium happens rather frequently and may even be associated with intraneural injection of © 2014 John Wiley & Sons Ltd Pediatric Anesthesia 25 (2015) 100–106
Wound installation and infiltration In common with many peripheral nerve blocks, the classic use of epinephrine as an adjunct will prolong the duration of analgesia even by local installation following inguinal surgery in children (39). The mechanism of action most likely being an increase in time that the long-acting local anesthetics is present at the site of action due to local vasoconstriction caused by the alpha-1 effect of epinephrine, thereby slowing systemic uptake of long-acting local anesthetics. In the context of tonsillectomy, local infiltration of ropivacaine together with clonidine in the tonsillar fossa prior to the start of surgery has been reported not only to increase the duration of immediate postoperative analgesia but also to reduce the pain on swallowing during the first five postoperative days (40). The mechanism behind this potentially ‘preemptive’ effect of clonidine when used for infiltration is obscure, and the effect reported by Gianonni et al. (40) has to date not been verified by any similar study. Local infiltration of ketamine has also been reported to be beneficial in children undergoing adeno-tonsillectomy (41). Side effects and safety The potential side effects and complications of adjunct use of morphine have already been mentioned above. Interestingly, the side effects of epidurally administered opioids can be ameliorated by the concomitant administration of adjunct clonidine (42). In this context, it may be added that systemic co-administration of clonidine will not potentiate the respiratory depression caused by morphine alone (43). Based on the published literature, the use of ketamine as adjunct to regional anesthesia appears to be associated with few and mild side effects. As there will be systemic uptake of the locally deposited ketamine, it should be remembered that the use of systemic ketamine has also been associated with the development of postoperative apnea in premature babies (44). The various effects that can/will result from the inevitable systemic uptake of adjunct clonidine (45) can mostly be viewed as positive spin-off effects rather than unwanted side effects (46). Clinically 103
€nnqvist P.-A. Lo
Adjuncts should always be used in pediatric regional anesthesia
Table 1 Suggestions on how to use adjuncts in daily clinical practice when performing pediatric regional anesthesia. All adjuncts must be preservative-free Type of block
Recommended adjuncts
Supporting references
Spinal block in expremature babies, neonates and infants Caudal blocks in ex-premature babies, neonates and infants
Clonidine 1 mcgkg 1 Clonidine 1 mcgkg 1 (Morphine 33–50 mcgkg 1, rarely indicated) S-ketamine 0.5 mcgkg 1 Clonidine 1–2 mcgkg 1 Clonidine >0.1 mcgkg 1h 1 Morphine 33–50 mcgkg 1, Intermittent injections 1–3 times daily Clonidine 1–2 mcgkg 1 Clonidine >0.1 mcgkg 1h 1
(28,61) (8,9,13,60,61)
Caudal blocks for children >1 years of age Continuous epidural analgesia with adequate segmental tip position Continuous epidural analgesia with suboptimal segmental tip position Peripheral nerve blocks, single injection Peripheral nerve blocks, continuous infusion
relevant reductions in heart rate and/or blood pressure are rare and easily treated (46). Prolongation of postoperative sedation after adjunct use of clonidine has not been specifically studied in children, but pediatric premedication even with high-dose clonidine (7–8 mcgkg 1) does not prolong postoperative sedation (47). Only one relevant case report exists linking the use of adjunct clonidine to postoperative apnea following awake caudal blockade in an ex-premature baby (48). However, any drug that will affect cerebral neurons may induce postoperative apnea in this specific patient population, and it should be remembered that the use of plain long-acting local anesthetics in this context is associated with altered EEG patterns during the time coinciding with maximum plasma concentrations of long-acting local anesthetics (49). Thus, even in this published case, it is very difficult to determine whether clonidine really was the causative agent. In general, clonidine can be viewed as a very safe alternative as accidental 100-fold overdosage in the setting of caudal anesthesia only resulted in the need for PICU observation (endotracheal intubation/mechanical ventilation was not needed) and was not associated with any signs of local toxicity (50). Potential effects on apoptosis in the spinal cord of very young individuals Although the best retrospective human registry studies have failed to identify any long-term effects of exposure to general anesthesia in early life (51,52), there are abundant animal data, including nonhuman primates (53– 55), which show increased cerebral apoptosis and later negative cognitive and behavioral consequences following exposure to anesthetics during the brain growth spurt period (56). However, the systemic co-administration of alpha-2 agonists in this context has been reported 104
(12,13,23) (31) (8,9) (35) (extrapolated from 31)
to reduce or ameliorate the neurotoxic effects of other anesthetic compounds (57,58). As the spinal cord forms part of the central nervous system, it appears likely that a similar apoptotic effect may be seen also in the spinal cord if exposed to anesthesia-related drugs during infancy. The possible apoptotic effect of spinal administration of anesthesia-related drugs has been investigated in a series of elegant rodent studies by Walker et al. (59– 62). In summary, these studies show that long-acting local anesthetics alone (levo-bupivacaine), clonidine, and preservative-free morphine are associated with a large safety margin between clinically effective dose and the dose associated with any toxic (apoptotic) effects (60–62). In sharp contrast, apoptosis was observed at doses needed to generate an analgesic response of ketamine, resulting in a therapeutic index
