The choice of local anesthetic must account for the duration of surgery, regional technique used, surgical requirements, potential for toxicity, and metabolic constraints (Tables 19.2 and 19.3).

1. Combinations of local anesthetics
   1. Mixtures of local anesthetics (eg, mepivacaine-bupivacaine) are asserted to accelerate onset, but data indicate that mixtures do not speed onset but do reduce duration.
   2. Mixture of non-bupivacaine local anesthetics with liposomal bupivacaine will perturb liposomes and alter the release of bupivacaine. A mixture of bupivacaine with liposomal bupivacaine alters the pharmacokinetics of release.
   3. Eutectic mixture of local anesthetics (EMLA) cream is a mixture of 2.5% lidocaine and 2.5% prilocaine for use as a topical skin anesthetic. It must be applied to unbroken, healthy skin for at least 30 minutes for an effect.
2. Adjuncts for local anesthesia
   1. Epinephrine: the most common additive after preservatives
      1. Benefits of epinephrine:
         1. To assist in the detection of intravascular injections.
         2. To decrease systemic toxicity by decreasing the rate of absorption of anesthetic into the circulation.
         3. To prolong the duration of anesthesia. This varies with the anesthetic agent, concentration, and block performed. Prolongation is inferior to other adjuvants.
      2. Limitations of epinephrine:
         1. Epinephrine is neurotoxic in diabetic animal models. Systemic epinephrine is dangerous in patients with severe coronary artery disease, arrhythmias, uncontrolled hypertension, and hyperthyroidism; it should be used with caution in susceptible populations.
         2. Epinephrine should be avoided in peripheral nerve blocks in areas with poor collateral blood flow (eg, digits, penis, and nose) or in intravenous local-anesthetic techniques.
      3. Fresh epinephrine can be added to make a 1:200,000 to 1:400,000 solution (2.5-5 μg/mL) prior to administration (while maintaining a high pH to speed onset of the block). Such a dilution is made by adding 0.5 to 0.1 mL (1 mg/mL) epinephrine to 20 mL of local anesthetic solution. These doses balance the detection of intravascular injection while minimizing the cardiovascular risk of higher doses of epinephrine.
      4. The maximum dose of epinephrine should not exceed 10 μg/kg in pediatric patients and 5 μg/kg in adults to avoid ventricular arrhythmias.
   2. Opioids including fentanyl, morphine, and hydromorphone are particularly useful in spinal/epidural anesthesia to prolong pain relief given that they bind to opioid receptors in the spinal cord but are less useful in peripheral nerve blocks.
      1. Buprenorphine can generate a 1.5- to 3-fold increase in the duration of peripheral blocks (0.15-0.3 mg or 3 μg/kg) but is associated with an increased risk of postoperative nausea and vomiting (PONV).
      2. Meperidine: Given its opioid and local anesthetic properties, it is used as the sole anesthetic agent in spinal anesthesia but avoided in the United States given the risk for serotonin syndrome from its metabolite norpethidine.
   3. Sodium bicarbonate raises the pH (from baseline of ~6 without epinephrine and ~4 with epinephrine) in order to increase the concentration of nonionized free base that can cross the membrane. This speeds the onset of neural blockade. Typically, 1 mEq of sodium bicarbonate is added to each 10 mL of lidocaine, chloroprocaine, or mepivacaine; only 0.1 mEq should be added to each 10 mL of bupivacaine to avoid precipitation.
   4. Alpha-2-agonists are central acting adrenergic agonists that bind presynaptic receptors (in the locus ceruleus and other sites) to produce anesthesia and analgesia. Higher doses are associated with sedation and bradycardia.
      1. Clonidine prolongs the duration of neuraxial anesthesia (15-50 μg single dose) with less benefit to regional anesthesia duration (100-150 μg or 0.5-5 μg/kg).
      2. Dexmetatomidine prolongs both neuraxial (intrathecal 5-10 μg, epidural 1 μg/kg) and regional anesthesia (20-150 μg) duration.
   5. Dexamethasone, an anti-inflammatory steroid extends the duration of regional blocks over intramuscular or intravenous injection of an equivalent dose of dexamethasone (neuraxial 4-8 mg, peripheral nerve block 1-8 mg).
   6. Magnesium, the N-methyl-D-aspartate agonist, provides a prolonged block duration (100-500 mg) but with concerns of increased PONV at higher doses.
   7. Other additives with little evidence and/or contraindications
      1. Phenylephrine has been used like epinephrine for local vasoconstriction but with limited clinical data and less utility as an intravascular marker.
      2. Tramadol: Multiple studies investigated tramadol with minimal benefit.