Factors Influencing Anesthetic Activity in Humans

Dosage of Local Anesthetic

As the dosage of local anesthetic is increased, the probability and duration of satisfactory anesthesia increase and the time to onset of blockade is shortened. The dosage of local anesthetic can be increased by administering either a larger volume or a more concentrated solution. For example, increasing the concentration of epidurally administered bupivacaine from 0.125% to 0.5% while maintaining the same volume of injectate (10 mL) results in shorter latency, an improved incidence of satisfactory analgesia, and a longer duration of sensory analgesia.^[49] The volume of anesthetic solution per se probably influences the spread of anesthesia. For example, 30 mL of 1% lidocaine administered into the epidural space produces

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Addition of Vasoconstrictors

Vasoconstrictors, usually epinephrine (5 µg/mL or 1:200,000), are frequently included in local anesthetic solutions to decrease the rate of vascular absorption, thereby allowing more anesthetic molecules to reach the nerve membrane and thus improving the depth and duration of anesthesia, as well as providing a marker for inadvertent intravascular injection.^[51] Epinephrine in a concentration of 1:200,000 has been reported to provide the optimal degree of vasoconstriction when used with lidocaine for epidural or intercostal application. ^[45] Other vasoconstrictors such as norepinephrine and phenylephrine have been used but do not appear to be superior to epinephrine. For example, equipotent concentrations, for vasoconstriction, of epinephrine and phenylephrine prolong the duration of spinal anesthesia produced by tetracaine to a similar extent.^[52]

The extent to which epinephrine prolongs the duration of anesthesia depends on the specific local anesthetic used and the site of injection. Epinephrine will significantly extend the duration of both infiltration anesthesia and peripheral nerve blocks with shorter-duration drugs (e.g., lidocaine).^{[53] [54]} Epinephrine does not markedly prolong the duration of motor blockade by epidural bupivacaine or etidocaine; however, it does modestly extend sensory blockade by these epidural drugs.^[40] The depth and duration of epidural analgesia in obstetric patients were improved slightly when epinephrine 1:300,000 was added to 0.25% bupivacaine.^[55] α-Adrenergic receptors in the spinal cord are known to activate endogenous analgesic mechanisms,^[56] and the increased depth of analgesic action produced by epinephrine and the α₂ -agonist clonidine with both epidural and intrathecal local anesthetics may arise both from this pharmacodynamic mechanism and from the pharmacokinetic (vasoconstrictive) action.

Site of Injection

The most rapid onset but the shortest duration of action occurs after intrathecal or subcutaneous administration of local anesthetics. The longest latencies and durations are observed after brachial plexus blocks. For example, intrathecal bupivacaine will usually produce anesthesia within 5 minutes that will persist for 3 to 4 hours. However, when bupivacaine is administered for brachial plexus blockade, the time of onset is approximately 20 to 30 minutes, and the duration of anesthesia (or at least analgesia) averages 10 hours. These differences in the onset and duration of anesthesia and analgesia are due in part to the particular anatomy of the area of injection, which will influence the rates of diffusion and vascular absorption and, in turn, affect the amount of drug used for various types of regional anesthesia. In the subarachnoid space, for example, the lack of a nerve sheath around the spinal cord and deposition of the local anesthetic solution in the immediate vicinity of the spinal cord are responsible for the rapid onset of action, whereas the relatively small amount of drug used for spinal anesthesia probably accounts for the short duration of conduction block.

On the other hand, the onset of brachial plexus blockade is slow because the anesthetic is usually deposited at some distance from the nerve and must diffuse through various tissue barriers before reaching the nerve membrane. The prolonged block with brachial plexus blockade may be related to several factors, including comparatively slow rates of vascular absorption from the brachial plexus sheath, larger doses of drug required for this regional anesthetic technique, and comparatively long segments of nerves exposed to local anesthetic.

Carbonation and pH Adjustment of Local Anesthetics

The addition of bicarbonate:carbon dioxide to a solution of local anesthetic applied to an isolated nerve accelerates the onset and decreases the minimum concentration (C_m ) required for conduction blockade.^{[57] [58] [59]} Although the effect of carbon dioxide on local anesthetic activity is easily demonstrable in isolated nerve,^{[57] [58]} controversy exists concerning the clinical utility of carbonated local anesthetic solutions. For example, some studies have failed to demonstrate a significantly more rapid onset of action for lidocaine carbonate than for lidocaine hydrochloride when used for epidural blockade,^[60] whereas others have reported a significant reduction in the time of onset of epidural blockade with lidocaine carbonate.^[61] Although the effect of carbon dioxide on accelerating the onset of epidural sensory and motor blockade has been equivocal, carbonated solutions appear to improve the depth of sensory and motor blockade.^{[60] [61]} In addition, these solutions may produce a more complete blockade of the radial, median, and ulnar nerves when used for brachial plexus blockade.^[62]

The addition of sodium bicarbonate to local anesthetic solutions has also been reported to decrease the time of onset of conduction blockade.^{[62] [63]} An increase in the pH of the local anesthetic solution increases the amount of drug in the uncharged base form, which should enhance the rate of diffusion across the nerve sheath and nerve membrane and result in a more rapid onset of anesthesia. Alkalinization of solutions of bupivacaine or lidocaine accelerated the onset of brachial plexus and epidural blockade in some studies,^{[62] [63]} but not others.^[64] Comparison among studies is difficult because of lack of uniform reporting on the pH or buffering capacity of the injected solutions and because inclusion of vasoconstrictors may strongly modify the actions of added bicarbonate.

Mixtures of Local Anesthetics

Mixtures of local anesthetics for regional anesthesia are sometimes used in an effort to compensate for the short duration of action of certain rapidly acting agents such as chloroprocaine and lidocaine and the long latency of longer-acting agents such as tetracaine and bupivacaine. Mixtures of chloroprocaine and bupivacaine theoretically offer significant clinical advantages because of the rapid onset and low systemic toxicity of chloroprocaine and the long duration of action of bupivacaine. A mixture of 3% chloroprocaine and 0.5% bupivacaine was reported to produce a short latency and prolonged duration of brachial

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Pregnancy (also see Chapter 58 )

The spread and depth of epidural and spinal anesthesia are reported to be greater in pregnant than nonpregnant women.^[68] This difference was originally attributed to mechanical factors associated with pregnancy (that is, dilated epidural veins decrease the volume of the epidural and subarachnoid spaces). Hormonal alterations probably play a more important role in the apparent increase in local anesthetic sensitivity during pregnancy because a greater spread of epidural anesthesia occurs during the first trimester of pregnancy, before any gross change in vascular dimensions within the epidural or subarachnoid space.^[69] A correlation appears to exist between progesterone concentrations in cerebrospinal fluid and the milligrams-per-segment requirement of lidocaine for spinal anesthesia in pregnant and nonpregnant patients. Lidocaine's block of sciatic nerve functions in pregnant rats significantly outlasts that in age-matched nonpregnant female or male rats,^[70] although pregnancy does not influence lidocaine uptake kinetics into nerves.^[70] These results suggest that the hormonal changes associated with pregnancy enhance the apparent potency of local anesthetics; thus, the dosage should probably be reduced in patients in all stages of pregnancy.