Pediatric Anesthesia 2004

14: 387393

Local anesthetics in infants and children: an update

C H A R LE S B E R D E
MD PhD

Division of Pain Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Childrens Hospital, Boston, and Harvard Medical School, Harvard, MA, USA

Keywords: anesthetics; local; mechanisms; epidural

Introduction
In the past 20 years, there has been much wider use of local anesthetics for infants and children. In the majority of cases, regional anesthesia for children undergoing surgery is performed in combination with general anesthesia, in order to provide postoperative analgesia. Major uses of local anesthetics for awake infants and children are the use of topical formulations on intact skin for needle procedures, use of topical formulations on cut skin for suture of lacerations, and use of inltration prior to deeper needle procedures or supercial minor surgical procedures. A series of publications described adaptation of techniques for epidural analgesia (1) and peripheral nerve blockade (2) in neonates, infants and children. As epidural blockade became more widely used for infants and children, case reports described several seizures and a few cardiac arrests during prolonged infusions of amino amide local anesthetics. In retrospect, the infusion rates used in these cases could have been predicted to be excessive, based on available single-dose pharmacokinetic data and on extrapolation of toxicity data from adults. Consideration of these cases led to predictions regarding maximum safe infusion rates for infants and children, which have been largely supported by
Speaker: Charles Berde, MD, Professor of Anaesthesiology and Paediatrics, Harvard Medical School; Chief, Division of Pain Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Childrens Hospital, Boston, MA, USA. Correspondence to: Charles Berde, c/o Pain Treatment Service, Childrens Hospital, 300 Longwood Ave, Boston, MA 02115, USA (email: charles.berde@childrens.harvard.edu). 2004 Blackwell Publishing Ltd

subsequent pharmacokinetic studies of prolonged epidural infusions in infants (3).

Local anesthetic mechanisms

All local anesthetics in current use are either amino amides or amino esters. Their predominant intended action is blockade of voltage gated sodium channels, and, thereby, blockade of impulse conduction in axons. Local anesthetics exert a range of other biological actions that may contribute to both local and systemic toxicities and to benecial systemic actions on inammatory responses or chronic pain conditions (4). They are low potency drugs that are administered in doses ranging up to hundreds of milligrams in adults. A simple picture of local anesthetic uptake and distribution is shown in Fig. 1. Note that for systemic drugs, the central circulation is in series between the injection site and the effect site, while for local anesthetics, unlike systemic medications, the effect site is in a parallel relationship with the central circulation: uptake into nerve from perineural injection sites competes with uptake into the central circulation. Direct measurements of intraneural concentrations of radiolabeled local anesthetics in animal models indicates that <23% of an injected dose ever enters the nerve, and within 30 min of injection, more than 90% of an injected dose is taken up into the systemic circulation (5). In order for local anesthetics to be effective, it is necessary for them to dissolve and diffuse readily in both aqueous environments, as found in cytosol and extracellular uid, and also in the hydrophobic environment of biological membranes. 387

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a
Injection or absorption site Central circulation Effect site

Metabolism and elimination

b
Injection or absorption site

> 98% of dose Central Circulation

2% of dose Metabolism and elimination

Effect Site (Nerve)

their consideration for clinical use, except when given in combination formulations (6,7), as will be described below. Vasoconstrictors are in general more effective for intensifying and prolonging the action of relatively hydrophilic local anesthetics than for relatively hydrophobic local anesthetics. Amino amides and amino esters both have a tertiary amine group that reversibly converts from an uncharged base form at alkaline pH to a protonated, charged form at acid pH. The pKas of local anesthetics are sufciently close to physiologic pH that a fraction of the molecules exist in both charged and uncharged forms, with rapid and reversible protonation. This feature permits rapid transmembrane diffusion of the uncharged base form and high aqueous solubility of the charged acid form. Local anesthetics exhibit use-dependent blockade. Nerves showing more rapid ring rates show greater susceptibility to blockade than nerves with low ring rates.

Figure 1 Heuristic models show basic differences in drug uptake, action and clearance between systemically acting drugs (a) and local anesthetics (b). Note that for perineural injection of local anesthetics, <2% of the dose enters the nerve, and most of the injected dose is taken up into the circulation (>90% within 30 min of injection). Small changes in permeability of drug to nerve or small changes in the initial rate of systemic uptake from perineural injection sites can dramatically alter block durations. Regional blood ow measurements following rat sciatic nerve blockade by Masuda et al. in our group (2004, manuscript under review) indicate that epinephrine prolongs blockade more by relatively brief reductions in blood ow in perineural injection sites, rather than by reductions in nerve blood ow. Perineural vasoconstriction slows the initial rapid systemic uptake from injection sites, thereby maintaining the concentration gradient for drug entry into nerve for a longer period of time.

Developmental changes in responses to local anesthetics Pharmacokinetics

All the amino amides, including bupivacaine, levobupivacaine, lidocaine, and ropivacaine show diminished clearance in neonates, with maturation over the rst 38 months of age (8,9). Future pharmacogenetic studies may identify cytochrome p450 polymorphisms that result in diminished metabolic inactivation of amino amides, or that result in a later time course of maturation of these enzyme systems. In addition, coadministration of drugs that inhibit or compete for cytochromes such as 3A4 and 2D6 may lead to clinically important elevation of local anesthetic blood concentrations. Limited information suggests that the amino esters, which are metabolized by plasma esterases, have very rapid clearance even in neonates. Our previous study of chloroprocaine in former preterm neonates undergoing inguinal hernia repair reported plasma concentrations generally below the limit of detection, and more than 10-fold below a threshold for systemic toxicity (extrapolated from animal studies and adult studies), even with infusion rates as high as 60 mgkg)1h)1 (10).
2004 Blackwell Publishing Ltd, Pediatric Anesthesia, 14, 387393

This structural constraint of having high solubility in both lipophilic and aqueous environments is one reason for the low potency of available amino amide and amino ester local anesthetics. There are a variety of naturally occurring toxins which show up to 1000-fold greater potency for blockade of sodium channels in isolated, desheathed nerves in vitro. However, these agents are either too hydrophilic to cross membranes rapidly (e.g. tetrodotoxin) or too lipophilic to dissolve adequately in aqueous media (e.g. veratridine), and their in vivo potency is sufciently low that systemic toxicity has limited

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Dose-scaling with body size

For most drugs in pediatrics, dosing is commonly scaled by body weight, although this relationship is often imprecise. In comparing the dose-response of bupivacaine or tetracaine for spinal anesthesia between neonates and adults, it became apparent that neonates require much larger (e.g. fourfold higher) weight-scaled doses to achieve a similar dermatomal level compared with adults, and that even with these much larger weight-scaled doses, the duration of action may be only one-third as long (1113). Some authors speculated that this trend was due to a higher weight-scaled volume of cerebrospinal uid in neonates compared with adults. However, studies from Hu, Kohane, and others in our group using an infant, adolescent and adult rat model of sciatic blockade showed similar trends (14,15), suggesting that the shorter block duration and requirement for larger weight-scaled doses to achieve blockade was a feature of peripheral nerve block as well, implying that the agerelated trends reported for spinal anesthesia dose response and duration may not be due simply to differences in distribution in cerebrospinal uid. There certainly may be age-related differences in pharmacodynamic responses, myelination, spacing of nodes of Ranvier, tissue barriers, and other factors. However, one factor that may be important is the dependence of minimal blocking concentration on length of nerve exposed to local anesthetic. Using an animal model in which varying lengths of nerve could be exposed to local anesthetic, Raymond et al. showed that the minimal blocking concentration decreases dramatically as the length of nerve exposed to local anesthetic is increased (16). As the length of nerve exposed is decreased to around two to three nodes of Ranvier, minimal blocking concentration increases dramatically. The implications of these ndings are shown in Fig. 2. The dose to block a nerve should depend to a signicant degree on the absolute length of nerve exposed, and this should scale weakly with body size. Conversely, if an infant nerve and adult nerve are exposed to a similar weight-scaled dose of local anesthetic, the adult nerve has a greater absolute length of nerve exposed, and thus it receives a relatively greater overdose compared with the infant nerve. If drug partitioning and rates of
2004 Blackwell Publishing Ltd, Pediatric Anesthesia, 14, 387393

Minimum Blocking Concentration

Length of nerve exposed to local anesthetic [Adapted from Raymond et al. (16)]

b Case # 1 Fixed dose (mg), independent of age or body size

Infant nerve Adult nerve

c Case # 2 Weight-scaled dosing (constant mg/kg)

Infant nerve

Adult nerve

Figure 2 Schematic models to explain why infants require larger weightscaled doses of local anesthetic than adults to achieve nerve blockade, and why infants, when given the same weight-scaled dose as adults, have shorter durations of nerve blockade. (a) Minimum blocking concentration for local anesthetics is greatly affected by the length of nerve exposed to local anesthetic (16). (b) This implies that the absolute dose of local anesthetic required to block a nerve should depend on length of nerve exposed to drug, and should be only weakly dependent on body size. (c) Conversely, if local anesthetic dosing is scaled by body weight (mgkg)1), then if adult and infant nerves receive the same concentration and the same weight-scaled dose, the adult nerve has a much longer length of nerve exposed. Other factors being equal, the adult nerve will, just on these scaling considerations, take longer than the infant nerve to have intraneural drug concentrations decay below minimum blocking concentration, i.e. the adult nerve will have longer duration nerve blockade than the infant nerve.

systemic uptake are similar between the infant and adult, then the infant nerve, with a shorter length of nerve exposed, will have its local anesthetic concentration in nerve decrease down below minimal blocking concentration sooner than the adult nerve, as the adult nerve, with its longer length of exposure, will have a much lower minimal blocking concentration than the infant nerve.

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Epidural analgesia: drug selection and use of additives in addition to local anesthetics
One of the attractions of epidural infusions is to minimize the side-effects associated with opioid analgesia. Because of the widespread concern regarding respiratory depression from opioids in infants, some clinicians have advocated using local anesthetics alone for epidural infusions in neonates and younger infants. The arguments in the previous section support the view that the therapeutic index of local anesthetics in infants may be sufciently narrow that maximum safe infusion rates of the amino amides are too low to provide sole analgesia for most major surgery in the thorax, abdomen or pelvis. Stated another way, infants require higher weight-scaled infusion rates than adults to achieve blockade, but they can only safely receive a lower weight-scaled infusion rate than adults, from the viewpoint of systemic toxicity. This would imply several approaches to improving efcacy in infants while maintaining safe local anesthetic dosing: 1 Combine local anesthetics with either opioids (17), clonidine (18), or S+ ketamine (19,20) in the epidural infusion, to provide synergistic analgesic effects while maintaining safe local anesthetic dosing. 2 Administer acetaminophen and either NSAIDs or COX-2 inhibitors round-the-clock to provide an additional systemic analgesic effect. 3 Permit low-dose intravenous opioids as rescue analgesics.

Improving technical success and safety in pediatric regional anesthesia

Regional anesthesia has a signicant technical failure rate in most case series. Attention to proper technique and insistence on objective methods to conrm placement can reduce the technical failure rates to acceptably low levels. As most pediatric blocks are performed after induction of general anesthesia, patient reports and examination for sensory and motor blockade are usually unavailable until the end of the surgical procedure, and emergence from general anesthesia. Many clinicians base their evaluation of an epidural on

hemodynamic responses and MAC-sparing effects intraoperatively. This approach is useful, but not infallible. When a patient with an epidural infusion arrives in pain in the postanesthetic care unit after a prolonged operation, it is crucial to conrm the location of the catheter tip and to provide analgesia rapidly. Administration of a systemic opioid or an epidural lipophilic opioid such as fentanyl will provide analgesia in many cases, but will not serve to conrm the location of the epidural catheter. In adults, a common intervention in this setting is to administer a repeat loading dose of an amino amide such as lidocaine or bupivacaine. In infants and smaller children, this should generally be avoided. As the child has received an initial loading dose and infusion of local anesthetic, they are likely to have blood concentrations not far from a threshold of toxicity. A second loading dose will then result in staircasing of blood concentrations, with a risk of seizures or cardiac depression. Our preferred approach in most cases is to test the catheter with incremental loading doses of chloroprocaine. If the chloroprocaine test conrms epidural placement, our general approach is to add a hydrophilic opioid such as hydromorphone to the epidural mixture, as it will spread cephalad as needed. Increasingly, hydromorphone has replaced fentanyl as the most commonly used opioid in epidural infusions in our hospital. A promising approach for conrming epidural catheter positioning, and to guide cephalad advancement in the epidural space, described by Tsui, involves use of electrically evoked motor responses using a wire-wrapped, saline-lled epidural catheter with a special adapter to permit transfer of electrical current to the catheter tip (21). For high risk patients, and for placement of longterm tunneled epidural or spinal catheters for patients with cancer (22) or chronic pain, my strong preference is to use uoroscopic guidance and injection of nonionic contrast media. In other more routine cases in which uoroscopy is already available in the room for surgeons use, imaging is sometimes helpful to conrm catheter placement in cases in which intraoperative dosing gives an equivocal anesthetic-sparing/hemodynamic response.

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Biological mechanisms of local anesthetic failure

Local anesthetics, even when administered in sufcient doses and with proper needle location, can fail to provide analgesia as a result of several processes, including tachyphylaxis, inammation-induced local anesthetic failure, and a recently described apparent resistance to blockade in some patients with complex regional pain syndromes and other forms of neuropathic pain. A prominent clinical observation regarding tachyphylaxis was made by Bromage, who showed that in parturients, the presence of pain in between repeat injections produced tachyphylaxis, while reinforcing the block before pain occurred prevented tachyphylaxis (23). This observation is difcult to interpret on any pharmacokinetic basis, and would suggest an effect related to hyperalgesia and spinal sensitization. Our group previously developed an animal model of tachyphylaxis using repeated sciatic blocks in rats. In this model, rats showed tachyphylaxis only if they were rendered hyperalgesic, and tachyphylaxis and hyperalgesia were both prevented by NMDA antagonists and nitric oxide synthase inhibitors (24), most probably acting at spinal sites (25). Note that what we observe clinically as effective epidural sensory blockade does not mean complete blockade of all impulses (26), only a degree of blockade that prevents sufcient summation in the spinal dorsal horn to generate ascending activity in spinal tracts that exceeds some threshold for perception. The interpretation of our animal studies is that in the presence of hyperalgesia, there is sufcient amplication of afferent signaling in the spinal cord that low rates of afferent impulses with partial peripheral conduction blockade now generate sufcient signaling to exceed perception thresholds. Experience in dentistry and emergency medicine indicates a high failure rate of local anesthesia in sites of infection or marked inammation (27). Studies in our group by Cairns et al. using rat models of brief inammatory or algesic substances suggest that both pharmacokinetic mechanisms [increased local blood ow accelerates systemic uptake from extraneural injection sites (see Fig. 1), edema increases diffusion distances for local anesthetic permeation into nerves, and local acidosis
2004 Blackwell Publishing Ltd, Pediatric Anesthesia, 14, 387393

impairs drug diffusion across biological membranes] and pharmacodynamic mechanisms (activation of peripheral as well as central NMDA receptors, direct effects of inammation on excitability of both peripheral nerves and spinal dorsal horn neurons) may be involved (2830). Recently, we described a subgroup of children with complex regional pain syndromes who showed three distinct patterns of apparent marked resistance to local anesthetic epidural or spinal blockade, despite radiographic conrmation of needle or catheter tip position (31). The mechanisms involved may relate to spinal sensitization, but further investigation is needed to better interpret these preliminary ndings. Pediatric anesthesiologists who care for children with complex regional pain syndromes should consider local anesthetic resistance, and not just ascribe failure of blockade to technical failure.

Newer and better drugs for the future?

Currently available local anesthetics have limitations, including local and systemic toxicities, insufcient sensory selectivity, and insufcient duration of analgesia following single-shot injection. One approach intended to reduce cardiotoxicity and improve sensory selectivity is to use single stereoisomers, including ropivacaine (15,19,3235) and levo-bupivacaine (36,37). These agents may provide modest increases in therapeutic index. Recent approaches to providing prolonged duration local anesthetics have included sustainedrelease delivery systems (3840) and combinations of site 1 sodium channel toxins with adrenergic agonists, amino amide local anesthetics, and other additives (6,7). Other groups have examined perineural injection of drugs previously used as systemic analgesics, such as amitriptyline and its derivatives (41), and ketamine and other excitatory amino acid receptor antagonists (29). A variety of sodium channels have been identied, cloned and sequenced. Some of these are expressed almost exclusively in small sensory bers, making these channels ideal targets for drug discovery as potential local anesthetics with much better sensory selectivity. Medline search did not identify such drugs in published preclinical trials.

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It remains to be determined which of these approaches will gain widespread clinical use in the future.

Conclusions
Local anesthetics are useful for a range of applications in infants and children. Recent research has elucidated developmental pharmacology of local anesthetics and has suggested approaches to safer and more effective use of these drugs. In the future, there may be ways to produce new local anesthetics that expand their utility for treatment of both acute and chronic pain.

Acknowledgements
This study was supported by the grants from NICHD, the Mayday Fund, Astra, Zars, and by the Anesthesia Pain Research Fund. Figures were adapted from presentations at the ASA Refresher Course lectures, 2002 and 2003.

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