Regional anesthesia in the pediatric population involves the injection of a relatively large volume of a concentrated local anesthetic solution into a compact anatomical space. The rate of absorption into the bloodstream is a major determinant of systemic toxicity. This has been studied predominantly for epidural/caudal anesthesia. Explicit detail on the kinetics of other routes of administration is lacking for this population. What is evident, though, for both central and peripheral blocks, is the more rapid rate of absorption from the cephalic parts of the body [4]; for example, a cervical epidural leads to higher plasma levels of local anesthetic than a caudal epidural. Similarly, absorption decreases from head to foot for peripheral conduction and infiltration blocks due to the relative difference in vascularity between these areas.

The main component of the epidural space is fat, which is an important determinant of local anesthetic systemic uptake. More lipophilic local anesthetic molecules will be retained to a greater degree by epidural fat leading to subsequent delayed absorption. It has been demonstrated in adults that after a single-shot epidural injection, 30 % of a dose of lidocaine and 50 % of a dose of bupivacaine remained in the epidural space for 3 h after injection [12]. The time to maximum peak plasma concentration (T_max) in infants for lidocaine and bupivacaine is 30 min after caudal or lumbar epidural injection [13]. Ropivacaine T_max is longer in infants than in children and longer in children compared to adults. In children aged 1–2 years, ropivacaine T_max is 115 min, whereas in children aged 5–8 years, ropivacaine T_max is closer to the adult value of 30 [14]. The vasoconstrictive properties of ropivacaine may contribute to its prolonged absorption from the epidural space. After T_max has been achieved, the rate of absorption slows down significantly so that it becomes longer than that of elimination, leading to a flip-flop effect in plasma drug concentration [4]. This continuous, protracted systemic absorption during the elimination phase, in combination with the buffering effect of plasma protein binding, limits the plasma concentration of unbound drug and is protective against toxicity.

Absorption rates at different block sites are directly related to local blood flow and inversely related to local tissue binding [15]. As a consequence, plasma uptake is faster from the more vascular intercostal space or the axilla than from the caudal space. Vascular uptake of local anesthetic after intercostal nerve block occurs more rapidly than with any other regional technique [16]. Despite recently published epidemiologic data indicating up to a fivefold increase in the utilization of peripheral nerve blockade in the pediatric population, specific pharmacokinetic data are lacking [17]. Ilioinguinal-iliohypogastric nerve blockade is the only peripheral block whose kinetics have been reported with any degree of regularity. Significantly higher plasma concentrations of both bupivacaine and ropivacaine have been reported in one study following ilioinguinal-iliohypogastric nerve block as compared to caudal blockade [18]. Times to peak plasma concentration were much faster for both drugs following ilioinguinal-iliohypogastric nerve block. The narrow inter-fascial space at this block location may facilitate absorption. This, coupled with greater uptake of local anesthetic into epidural fat, may account for the lower plasma levels seen after caudal injection.

Local anesthetics are distributed to the tissues and body fluid compartments after systemic absorption to the plasma. Volume of distribution (Vd) is a mathematical expression which depicts the distribution characteristics of a drug in the body. It is a measure of the degree to which a drug is delivered by the plasma to the organs and tissues of the body. Drugs with a small calculated Vd have a high concentration of drug in the plasma, have a concomitant low tissue concentration, and are more likely to accumulate to toxic levels. Drugs with a larger Vd are subject to slower elimination. Vd is influenced by degree of ionization/lipophilicity, plasma protein binding, and molecular size [19]. Since local anesthetics are weak bases that have dissociation constants (pKa values) above physiological pH, more than 75 % of the commonly used amide local anesthetic drugs exist in a hydrophilic ionized form at physiological pH (Table 7.1). Hence, they are highly water-soluble molecules but are less likely to cross lipid cell membranes. As a result of the delayed systemic absorption of local anesthetic drugs, it is impossible to calculate a volume of distribution with any accuracy. One study found bupivacaine to have a higher Vd in neonates and infants [20], which may be related to the higher fraction of unbound drug to plasma protein (see next section). Following adult epidural anesthesia, ropivacaine appears to have a smaller Vd than bupivacaine [21, 22], and indirect evidence points to a similarly reduced Vd in infants. Following single-shot caudal anesthesia, peak concentration of ropivacaine is higher than bupivacaine [23]. Two further studies have demonstrated that Vd of ropivacaine appears slightly smaller before the age of four [14, 24].

Local anesthetic is distributed to organs according to their vascular density. The local anesthetic is taken up within each organ according to the tissue-plasma partition coefficient (Table 7.3). The lungs play an important buffering role by taking the full impact of drug-laden venous blood. A variety of investigational techniques, including autoradiography, scintillation counts, and tissue assays, confirm the lung’s ability to quickly extract local anesthetic [25], although this buffering action of the lung is saturable.

Local anesthetics bind tightly to serum proteins, greatly limiting the free fraction of available drug. This is clinically relevant as it is only the free or unbound fraction that is bioactive (i.e., readily available to cross cell membranes to become active at the sodium channel). Volume of distribution (see above) is inversely related to protein binding. Drugs which are highly protein-bound have limited passage into tissues resulting in a high drug plasma concentration and a low Vd. In adults, lidocaine is up to 70 % protein bound while bupivacaine, levobupivacaine, and ropivacaine are over 90 % protein bound [19].

Three principal blood components are involved in local anesthetic binding: the plasma proteins alpha-1-acid glycoprotein (AAG), human serum albumin (HSA), and erythrocytes. Like most weak bases, local anesthetics bind mainly to AAG. AAG has a greater affinity for binding local anesthetic by an order of magnitude of 5,000–10,000 compared to albumin [26]. Capacity for binding is relatively low, however, and saturation occurs at clinically relevant concentrations. Even though albumin is the most abundant plasma protein (50–80 times more abundant than AAG), it has a low affinity for amide local anesthetic drugs [4]. By virtue of its enormous binding capacity (it is almost unsaturable), together with its abundance, the role of HSA becomes significant when AAG is saturated.