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Adjuvants in pediatric regional anesthesia
Practice Points
Adrian Bosenberg* Local anesthetics have a limited duration of action unless given by continuous infusion. Adjuvants are used to prolong the duration and quality of neuraxial analgesia or to allow lower
concentrations of local anesthetic to be used for infusions. Opiates, particularly morphine, have been the gold-standard but they are less popular in view of the
unwanted side effects; sedation, nausea, vomiting, pruritis and respiratory depression. Clonidine is most popular because it has fewer side effects. The jury is still out with regard to the neurotoxicity (ketamine) and the histopathological changes seen
with some adjuvants but these may be related to the preservatives (e.g., benzethonium chloride and chlorbutanol). Many other adjuvants (midazolam, neostigmine and buprenorphine) have been tested, mostly off-label and
without proper preclinical trials, but the side effects outweigh the benefits therefore limiting clinical use. Adjuvants, particularly clonidine, have also been used to supplement peripheral nerve blocks but the
evidence to support its use in children is still weak.
SUMMARY
Local anesthetics have a limited duration of action. Adjuvants are used to prolong the duration of action and to augment analgesia allowing lower concentrations of local anesthetic to be used. Adjuvants have been used more extensively with neuraxial blocks, particularly caudal epidural blocks, but more recently to supplement peripheral nerve blocks. Intrathecal adjuvants are not covered in this review since spinal anesthesia is not widely used in children except in ex-premature infants. Morphine is the historical gold-standard with which other adjuvants are compared. Clonidine is most useful and is becoming increasingly popular, while the side-effect profile of other agents reduces their utility. Concerns with regard to the neurotoxicity of ketamine in animal models has led to its withdrawal in some countries. Single shot caudals with bupivacaine, ropivacaine or levobupivacaine are safe and effective but only provide analgesia for 4–6 h [1] . Since continuous infusions of local anesthetic
agents have a relatively narrow margin of safety in young infants and children, a variety of agents have been used as adjuvants in an attempt to prolong the analgesic efficacy
*Department of Anesthesiology & Pain Management, Faculty of Health Sciences, University of Washington, Seattle, USA and Seattle Children’s Hospital, 4800 Sandpoint Way NE, Seattle, WA 98105, USA; [email protected]
10.2217/PMT.12.51 © 2012 Future Medicine Ltd
Pain Manage. (2012) 2(5), 479–486
part of
ISSN 1758-1869
479
Review Bosenberg of caudal, neuraxial and peripheral nerve blockade [2–7] . Adjuvants are drugs that increase the efficacy or potency of other drugs when given concurrently. Adjuvants can be used to prolong the duration of analgesia after single shot caudal blocks, and to improve the quality of the analgesia while allowing lower local anesthetic concentrations to be used [8] , thereby reducing unwanted side effects of local anesthetics such as motor blockade. Furthermore, the risk of local anesthetic toxicity is also reduced since a lower concentration can be used; in effect, less drug is administered, a lower peak plasma concentration (lower free fraction) is reached more slowly, therefore, there is a lower risk of toxicity. Overview In choosing an adjuvant the anesthesia provider must balance the benefits against the potential risks, taking the age of the child and the impact of comorbidities into account. The facilities, level of staffing available, and whether the child is to be managed at home or in hospital must also be considered. Based on current evidence it is difficult to reach consensus on the most effective adjuvant and there is even less evidence when combinations are used. Most studies in children have used minor surgery (e.g., inguinal hernia repair and circumcision) under caudal block as the clinical research model. Adjuvants have been the subject of a number of meta-analyses recently [9–12] . The heterogeneity of the studies, both in terms of the type, volume and concentration of local anesthetic agent as well as the dose of adjuvant used, are all confounding factors that make meta-analyses difficult [9–13] . The studies also vary in the nature of surgery, the premedication used, supplementary analgesia, the method of pain assessment and the age range of the children [12] . Most recently, Engelman and Marsala used statistical methods to overcome the heterogeneity of analgesic treatments by using an index of treatment efficacy that is independent of the units used on a pain scale [12] . These methods are apparently most useful when reviewing studies on adjuvants, for example, where the same effect is expressed using scales that are not easily interchangeable [12] . Can the findings in inguinal surgery be extrapolated to major abdominal or thoracic surgery? Significantly, there are relatively few
480
Pain Manage. (2012) 2(5)
reports of the use of additives for major surgery in children despite their popularity. Those that have been reported demonstrated lower pain scores when compared with local anesthetic alone. Some suggest that opiate adjuvants should only be used for major surgery (e.g., spinal surgery and liver surgery) to enhance the effect of epidural infusions that may be inadequate, or to supplement an epidural infusion when adequate spread of local anesthetic cannot be achieved within safe dosage limits. Recent surveys of members of the Association of Paediatric Anaesthetists of Great Britain and Ireland (APAGBI) show an increased use of adjuvants to enhance the analgesia provided by a caudal block from 58% [13] to almost 80% [14] over the past decade. Other centers surveyed report an increased use in clonidine since the withdrawal of ketamine in some countries (Germany, Austria, Switzerland and the USA) precipitated by the reports of neurotoxic effects in animals [15–17] . The results of the latest UK survey are awaited with interest [101] . Although many agents have been studied, the most effective agents in clinical practice are opiates (morphine, diamorphine), clonidine and ketamine. Clonidine is steadily becoming more popular [15] , while opiates, despite their efficacy, seem to be on the decline primarily because of their unwanted side effects [13,14] . Ketamine is likely to suffer the same fate until the issue of neurotoxicity has been resolved. Central neuraxial blocks Opioids
Opioids act as agonists of receptors that are widespread throughout the body including the brain (cerebral cortex, thalamus, hypothalamus, amygdala, basal ganglia, brainstem and reticular activating system), spinal cord and non-neural tissues such as the GI tract. There are four main classes of opioid receptors; mu, kappa, delta and nociceptin – all of which are G-protein-coupled inhibitory receptors. Analgesia from neuraxial opioid administration is primarily mediated by binding pre- and post-synaptic µ-opioid receptors in the substantia gelatinosa of the dorsal horn of the spinal cord. Morphine is considered the gold-standard while other opiates (fentanyl, sufentanil, hydromorphone, diamorphine and buprenorphine) have their proponents. Each opioid has a different affinity for each class of receptor and each receptor is associated with specific therapeutic
future science group
Adjuvants in pediatric regional anesthesia and adverse effects. While the synergistic analgesic effect of opiates and local anesthetic agents is well recognized and they may prolong analgesia for up to 24 h, the optimal choice of opiate is still a matter of debate. All opiates are associated with unwanted side effects (respiratory depression, nausea, vomiting, reduced gut motility, pruritis and urinary retention) to a varying degree [2,4,7,18–21] . Morphine (bolus 20–30 µg/kg, continuous infusion 1 µg/kg/h) has been shown to be effective; higher doses are associated with increasing incidence of apnea and respiratory depression particularly when parenteral opiates have been administered concurrently [7] . Hydrophilic morphine can be placed at a lower metameric level to provide analgesia. Ideally, lipophilic agents (sufentanil and fentanyl – bolus 0.2 µg/kg; infusion 1 µg/kg/h) should be placed at the metameric level of the pain for optimum effect. Urinary retention and pruritus can be managed with intravenous naloxone 1 µg/kg, and if necessary by continuous infusion 1–2 µg/kg/h [22] or an intravenous dose of nalbuphine 0.1 mg/kg. To date, there is no evidence in animal studies that intrathecal morphine has neurotoxic effects [23] . Fentanyl (1 µg/kg), on the other hand, does not prolong the duration of analgesia when added to ‘single-shot’ caudal for inguinal surgery [24,25,27] but significantly increases the incidence of nausea and vomiting compared with local anesthetic alone. Following more extensive vesico-ureteric reflux surgery, significant enhancement of analgesia was recorded [26] . A negative aspect of adding fentanyl to epidural infusions of bupivacaine in infants undergoing thoracotomy is that it may prolong recovery and increase the incidence of adverse respiratory events without providing a significant analgesic benefit [28,29] . Sufentanil is a more potent lipophilic thienyl analog of fentanyl with higher µ-receptor affinity and specificity. The studies in children are limited and the heterogeneity of dosage used and supplementary local anesthetic solutions make comparisons difficult [30–33] . Sufentanil has a relatively low incidence of side effects particularly delayed respiratory depression, although drowsiness is common [34,35] . Sufentanil has a rapid onset (3 min) but a relatively short duration of action (3 h) [34] . It is therefore more ideally suited for continuous infusion and patient-controlled epidural analgesia in age- and cognitive-appropriate children [35] . Sufentanil
future science group
Review
provides better quality analgesia than fentanyl [36] . An initial bolus of 0.5–1 µg/kg, and subsequent infusion of 0.1–0.3 µg/kg/h, provides satisfactory analgesia for both abdominal and thoracic surgery. Recently, opiate adjuvants seem to have been superceded by clonidine and ketamine [9,10,12,15,37] . Alpha-2-agonists
Clonidine, an alpha-2-agonist with sedative, analgesic and antihypertensive properties, is commercially available as a preservative-free preparation. There is good evidence that the major effect of clonidine is mediated at the spinal-cord level [38,39] . Clonidine 1–2 µg/kg is effective. Higher doses are associated with increasing sedation, bradycardia, hypotension and a risk of apnea, particularly in neonates and infants although increased side effects are not limited to higher dose ranges. Clonidine (0.1 µg/kg/h) enhances the analgesia of dilute continuous epidural infusions of bupivacaine or ropivacaine 0.1% [9,26,40] . A meta-analysis of 20 ������������������� randomized controlled trials (published between 1994 and 2010) including 993 children aged 2–6 years old undergoing urogenital or lower-limb surgery demonstrated a longer duration of postoperative analgesia in those receiving clonidine 1 µg/kg in addition to local anesthetic (mean duration: 3.72 h; 95% CI: 2.61–4.84; p
Adjuvants in pediatric regional anesthesia
Practice Points
Adrian Bosenberg* Local anesthetics have a limited duration of action unless given by continuous infusion. Adjuvants are used to prolong the duration and quality of neuraxial analgesia or to allow lower
concentrations of local anesthetic to be used for infusions. Opiates, particularly morphine, have been the gold-standard but they are less popular in view of the
unwanted side effects; sedation, nausea, vomiting, pruritis and respiratory depression. Clonidine is most popular because it has fewer side effects. The jury is still out with regard to the neurotoxicity (ketamine) and the histopathological changes seen
with some adjuvants but these may be related to the preservatives (e.g., benzethonium chloride and chlorbutanol). Many other adjuvants (midazolam, neostigmine and buprenorphine) have been tested, mostly off-label and
without proper preclinical trials, but the side effects outweigh the benefits therefore limiting clinical use. Adjuvants, particularly clonidine, have also been used to supplement peripheral nerve blocks but the
evidence to support its use in children is still weak.
SUMMARY
Local anesthetics have a limited duration of action. Adjuvants are used to prolong the duration of action and to augment analgesia allowing lower concentrations of local anesthetic to be used. Adjuvants have been used more extensively with neuraxial blocks, particularly caudal epidural blocks, but more recently to supplement peripheral nerve blocks. Intrathecal adjuvants are not covered in this review since spinal anesthesia is not widely used in children except in ex-premature infants. Morphine is the historical gold-standard with which other adjuvants are compared. Clonidine is most useful and is becoming increasingly popular, while the side-effect profile of other agents reduces their utility. Concerns with regard to the neurotoxicity of ketamine in animal models has led to its withdrawal in some countries. Single shot caudals with bupivacaine, ropivacaine or levobupivacaine are safe and effective but only provide analgesia for 4–6 h [1] . Since continuous infusions of local anesthetic
agents have a relatively narrow margin of safety in young infants and children, a variety of agents have been used as adjuvants in an attempt to prolong the analgesic efficacy
*Department of Anesthesiology & Pain Management, Faculty of Health Sciences, University of Washington, Seattle, USA and Seattle Children’s Hospital, 4800 Sandpoint Way NE, Seattle, WA 98105, USA; [email protected]
10.2217/PMT.12.51 © 2012 Future Medicine Ltd
Pain Manage. (2012) 2(5), 479–486
part of
ISSN 1758-1869
479
Review Bosenberg of caudal, neuraxial and peripheral nerve blockade [2–7] . Adjuvants are drugs that increase the efficacy or potency of other drugs when given concurrently. Adjuvants can be used to prolong the duration of analgesia after single shot caudal blocks, and to improve the quality of the analgesia while allowing lower local anesthetic concentrations to be used [8] , thereby reducing unwanted side effects of local anesthetics such as motor blockade. Furthermore, the risk of local anesthetic toxicity is also reduced since a lower concentration can be used; in effect, less drug is administered, a lower peak plasma concentration (lower free fraction) is reached more slowly, therefore, there is a lower risk of toxicity. Overview In choosing an adjuvant the anesthesia provider must balance the benefits against the potential risks, taking the age of the child and the impact of comorbidities into account. The facilities, level of staffing available, and whether the child is to be managed at home or in hospital must also be considered. Based on current evidence it is difficult to reach consensus on the most effective adjuvant and there is even less evidence when combinations are used. Most studies in children have used minor surgery (e.g., inguinal hernia repair and circumcision) under caudal block as the clinical research model. Adjuvants have been the subject of a number of meta-analyses recently [9–12] . The heterogeneity of the studies, both in terms of the type, volume and concentration of local anesthetic agent as well as the dose of adjuvant used, are all confounding factors that make meta-analyses difficult [9–13] . The studies also vary in the nature of surgery, the premedication used, supplementary analgesia, the method of pain assessment and the age range of the children [12] . Most recently, Engelman and Marsala used statistical methods to overcome the heterogeneity of analgesic treatments by using an index of treatment efficacy that is independent of the units used on a pain scale [12] . These methods are apparently most useful when reviewing studies on adjuvants, for example, where the same effect is expressed using scales that are not easily interchangeable [12] . Can the findings in inguinal surgery be extrapolated to major abdominal or thoracic surgery? Significantly, there are relatively few
480
Pain Manage. (2012) 2(5)
reports of the use of additives for major surgery in children despite their popularity. Those that have been reported demonstrated lower pain scores when compared with local anesthetic alone. Some suggest that opiate adjuvants should only be used for major surgery (e.g., spinal surgery and liver surgery) to enhance the effect of epidural infusions that may be inadequate, or to supplement an epidural infusion when adequate spread of local anesthetic cannot be achieved within safe dosage limits. Recent surveys of members of the Association of Paediatric Anaesthetists of Great Britain and Ireland (APAGBI) show an increased use of adjuvants to enhance the analgesia provided by a caudal block from 58% [13] to almost 80% [14] over the past decade. Other centers surveyed report an increased use in clonidine since the withdrawal of ketamine in some countries (Germany, Austria, Switzerland and the USA) precipitated by the reports of neurotoxic effects in animals [15–17] . The results of the latest UK survey are awaited with interest [101] . Although many agents have been studied, the most effective agents in clinical practice are opiates (morphine, diamorphine), clonidine and ketamine. Clonidine is steadily becoming more popular [15] , while opiates, despite their efficacy, seem to be on the decline primarily because of their unwanted side effects [13,14] . Ketamine is likely to suffer the same fate until the issue of neurotoxicity has been resolved. Central neuraxial blocks Opioids
Opioids act as agonists of receptors that are widespread throughout the body including the brain (cerebral cortex, thalamus, hypothalamus, amygdala, basal ganglia, brainstem and reticular activating system), spinal cord and non-neural tissues such as the GI tract. There are four main classes of opioid receptors; mu, kappa, delta and nociceptin – all of which are G-protein-coupled inhibitory receptors. Analgesia from neuraxial opioid administration is primarily mediated by binding pre- and post-synaptic µ-opioid receptors in the substantia gelatinosa of the dorsal horn of the spinal cord. Morphine is considered the gold-standard while other opiates (fentanyl, sufentanil, hydromorphone, diamorphine and buprenorphine) have their proponents. Each opioid has a different affinity for each class of receptor and each receptor is associated with specific therapeutic
future science group
Adjuvants in pediatric regional anesthesia and adverse effects. While the synergistic analgesic effect of opiates and local anesthetic agents is well recognized and they may prolong analgesia for up to 24 h, the optimal choice of opiate is still a matter of debate. All opiates are associated with unwanted side effects (respiratory depression, nausea, vomiting, reduced gut motility, pruritis and urinary retention) to a varying degree [2,4,7,18–21] . Morphine (bolus 20–30 µg/kg, continuous infusion 1 µg/kg/h) has been shown to be effective; higher doses are associated with increasing incidence of apnea and respiratory depression particularly when parenteral opiates have been administered concurrently [7] . Hydrophilic morphine can be placed at a lower metameric level to provide analgesia. Ideally, lipophilic agents (sufentanil and fentanyl – bolus 0.2 µg/kg; infusion 1 µg/kg/h) should be placed at the metameric level of the pain for optimum effect. Urinary retention and pruritus can be managed with intravenous naloxone 1 µg/kg, and if necessary by continuous infusion 1–2 µg/kg/h [22] or an intravenous dose of nalbuphine 0.1 mg/kg. To date, there is no evidence in animal studies that intrathecal morphine has neurotoxic effects [23] . Fentanyl (1 µg/kg), on the other hand, does not prolong the duration of analgesia when added to ‘single-shot’ caudal for inguinal surgery [24,25,27] but significantly increases the incidence of nausea and vomiting compared with local anesthetic alone. Following more extensive vesico-ureteric reflux surgery, significant enhancement of analgesia was recorded [26] . A negative aspect of adding fentanyl to epidural infusions of bupivacaine in infants undergoing thoracotomy is that it may prolong recovery and increase the incidence of adverse respiratory events without providing a significant analgesic benefit [28,29] . Sufentanil is a more potent lipophilic thienyl analog of fentanyl with higher µ-receptor affinity and specificity. The studies in children are limited and the heterogeneity of dosage used and supplementary local anesthetic solutions make comparisons difficult [30–33] . Sufentanil has a relatively low incidence of side effects particularly delayed respiratory depression, although drowsiness is common [34,35] . Sufentanil has a rapid onset (3 min) but a relatively short duration of action (3 h) [34] . It is therefore more ideally suited for continuous infusion and patient-controlled epidural analgesia in age- and cognitive-appropriate children [35] . Sufentanil
future science group
Review
provides better quality analgesia than fentanyl [36] . An initial bolus of 0.5–1 µg/kg, and subsequent infusion of 0.1–0.3 µg/kg/h, provides satisfactory analgesia for both abdominal and thoracic surgery. Recently, opiate adjuvants seem to have been superceded by clonidine and ketamine [9,10,12,15,37] . Alpha-2-agonists
Clonidine, an alpha-2-agonist with sedative, analgesic and antihypertensive properties, is commercially available as a preservative-free preparation. There is good evidence that the major effect of clonidine is mediated at the spinal-cord level [38,39] . Clonidine 1–2 µg/kg is effective. Higher doses are associated with increasing sedation, bradycardia, hypotension and a risk of apnea, particularly in neonates and infants although increased side effects are not limited to higher dose ranges. Clonidine (0.1 µg/kg/h) enhances the analgesia of dilute continuous epidural infusions of bupivacaine or ropivacaine 0.1% [9,26,40] . A meta-analysis of 20 ������������������� randomized controlled trials (published between 1994 and 2010) including 993 children aged 2–6 years old undergoing urogenital or lower-limb surgery demonstrated a longer duration of postoperative analgesia in those receiving clonidine 1 µg/kg in addition to local anesthetic (mean duration: 3.72 h; 95% CI: 2.61–4.84; p
