Peripheral Nerve Blocks: A Color Atlas, 3rd Edition

3.Local Anesthetic Solutions

Andrea Casati

A. Local Anesthetics

General Overview

Local anesthetics block the generation and conduction of nerve impulses at the level of the cell membrane. They bind directly within the intracellular portion of voltage-gated sodium channels in their ionized form when the channels are open. The penetration of local anesthetics through the channels depends on the ionized form and therefore their relative hydrophilicity. On the other hand, the local anesthetic diffusion across membrane depends on the molecular weight and the liposolubility of the molecule. Because all local anesthetics have almost the same molecular weight, the diffusibility of the local anesthetic molecules from the injection site depends on their hydrophilicity. The hydrophilic and nonionized form of the molecule is more lipid soluble than the ionized one and can therefore cross the cell membrane more easily but diffuses less easily. Thus, local anesthetics with a higher pKa are more likely to be ionized at physiologic pH than drugs with a lower pKa; therefore, they are typically more potent at the neuronal sites but are also more likely to be absorbed before reaching the neuronal tissue. Moderate hydrophobicity is required for passing through the neuronal sheath.

The choice for a local anesthetic solution is based on the expected onset time, the desired duration of the block, the need to produce a preferential sensory, and the relative toxicity of the mixture. These characteristics are primarily determined by their physicochemical properties, described as follows:

· The potency of local anesthetic is primary determined by its lipid solubility (expressed as lipid/water partition coefficient). Unfortunately, the potential for toxicity also depends on lipid solubility; accordingly, more lipophilic agents are more potent but also have a more pronounced potential for systemic toxicity.

· The onset time of local anesthetics is influenced by the molecule's pKa (the higher the pKa, the slower the onset time of the nerve block in a physiologic environment) and diffusibility.

· The degree of protein binding affects the duration of action.

· The age of the patient has also been demonstrated to affect the duration of a block: duration of action is shorter in young patients compared with older patients.

 

Table 3-1. Amide and Ester-type Local Anesthetics Used for Peripheral Nerve Blocks

Amides

Esters

Lidocaine

Chloroprocaine

Bupivacaine

Prilocaine

Ropivacaine

Tetracaine

Levobupivacaine

Articaine

Mepivacaine

In general, small nerve fibers are more sensitive to local anesthetics than are large nerve fibers. However, myelinated fibers are blocked before nonmyelinated fibers of the same diameter. Autonomic fibers, small unmyelinated C fibers, and small myelinated A-δ fibers are blocked before larger myelinated A-γ, A-β, or A-α fibers. Clinically, the loss of nerve function typically progresses as do loss of pain, temperature, touch, proprioception, and skeletal muscle tone.

There are two classes of local anesthetics: amides and esters (Table 3-1). The primary differences between the two classes are in their relative metabolism (amides have primarily a hepatic metabolism, whereas esters are metabolized by plasma cholinesterases) and their potential for allergic reactions (esters have a greater potential than do amides).

Important differences can be found among local anesthetics within the same class, primarily regarding their onset, duration of action, and potential for toxicity. Clinical characteristics of local anesthetics, onset time, duration of the block, and even toxicity vary significantly according to the type of block, the approach, the concentration of the local anesthetic solution, and the volume administered. Table 3-2 describes the onset time and duration of different nerve blocks with a number of local anesthetic solutions.

Treatment of Local Anesthetic Toxicity

To treat adverse reactions and toxicity:

1. Stop the administration of local anesthetic.

2. Maintain a patent airway.

3. Assist or control ventilation with oxygen.

4. Intralipid administration (intralipid 20% 1.5 mg/kg over 1 minute, followed immediately with an infusion at a rate of 0.25 mg/kg/min. Continue chest compression in case of cardiac arrest. Repeat bolus every 3–5 min up to 3 mL/kg total dose until circulation is restored. Continue infusion until hemodynamic stability is restored. Increase the rate to 0.5 mL/kg/min. The maximum total dose of 8 mL/kg is recommended). www.lipidrescue.org

5. Treat signs of central nervous system toxicity with either intravenous benzodiazepines (e.g., diazepam 0.1 to 0.2 mg/kg, midazolam 2 to 5 mg) or thiopental 1 to 2 mg/kg.

6. Treat with succinylcholine (1 mg/kg) to terminate a state of generalized convulsions.

7. Treat hypotension with intravenous fluids or vasopressors.

8. Treat circulatory collapse with positive inotropic effects such as amiodarone. Avoid ephedrine or epinephrine with peripheral vasoconstrictor effects at the same time.

9. Institute cardiopulmonary resuscitation (CPR).

10.     Consider cardiopulmonary bypass if the aforementioned measures are unsuccessful.

Toxicity of Local Anesthetics

Though rare, administration of local anesthetic can produce allergic reactions. These reactions are mostly related to aminoester drugs. The allergic reaction is related to the preservative, the para-aminobenzoic acid. Nonetheless, risk for allergic reactions is present also with aminoamide anesthetic, especially when using formulations containing preservatives or antibacterial additives, like those in multidose preparations.

 

Table 3-2. Reference Guide of Local Anesthetics for Peripheral Nerve Blocks

Nerve Block

Expected Onset of Surgical Anesthesia

Expected Duration of Surgical Anesthesiac

Local Anesthetic/Additive to Usea,b

Cervical plexus block

15–20 min

1.0–1.5 h
1.5–2.0 h
3.0–4.0 h

Mepivacaine or lidocaine 1.5%
Mepivacaine or lidocaine 1.5% + epi
Ropivacaine. bupivacaine, or levobupivacaine 0.5%

Upper extremity blocks:

Brachial plexus:

Interscalene

10–15 min

≤1.0 h

Chloroprocaine 3%

Intraclavicular

 

≤2.0 h

Chloroprocaine 3% + epi

 

10–15 min

1.5–3.0 h

Mepivacaine or lidocaine 1.5%

Axillary

   

Mepivacaine or lidocaine 1.5% + epi

Elbow and wristd

10–20 min

2.0–4.0 h

Ropivacaine, levobupivacaine, or bupivacaine 0.5%

 

10–20 min

3.0–5.0 h

Ropivacaine, levobupivacaine, or bupivacaine 0.5% + epi

 

10–20 min

3.0–4.0 h

Mixture of mepivacaine or lidocaine 1.5% and ropivacaine 0.75%

Lower extremity blocks:

10–15 min

≤1.0 h

Chloroprocaine 3%

Lumbar plexus

10–20 min

2.0–3.0 h

Mepivacaine or lidocaine 1.5%

Femoral

15–20 min

3.0–4.0 h

Ropivacaine, levobupivacaine, or bupivacaine 0.5%

 

10–20 min

2.0–4.0 h

Mixture of mepivacaine or lidocaine 1.5% and ropivacaine 0.75%

Sciatic block

10–15 min

1.5–2.0 h

Chloroprocaine 3%

 

10–20 min

2.0–3.0 h

Mepivacaine or lidocaine 1.5%

 

15–20 min

3.0–4.0 h

Ropivacaine, levobupivacaine, or bupivacaine 0.5%

 

10–20 min

3.0–4.0 h

Mixture of mepivacaine or lidocaine 1.5% and ropivacaine 0.75%

Popliteal block

10–20 min

≤1.0 h
3.0–4.0 h
3.0–4.0 h

Chloroprocaine 3%
Mepivacaine or lidocaine 1.5%
Ropivacaine, levobupivacaine, or bupivacaine 0.5%
Mixture of mepivacaine or lidocaine 1.5% and ropivacaine 0.75%

Ankle block

15–30 min

3.0–4.0 h

Ropivacaine, levobupivacaine, or bupivacaine 0.25%

Thoracic and lumbar paravertebral block

10–20 min

2.0–3.0 h

Ropivacaine, levobupivacaine, or bupivacaine 0.5%

Intravenous block

10–15 min
10–20 min

2.0–3.0 h

Lidocaine 0.5%
Ropivacaine 0.2%, levobupivacaine 0.15%

Eye block

10–15 min

1.5–2.0 h

Lidocaine 1%

epi = epinephrine.
Source: Adapted with permission from the New York School of Regional Anesthesia. Available at: www.NYSORA.com. Accessed April 30, 2003. Indicates the range of expected onset and duration of action.

aThe choice of local anesthetic is based on the authors' clinical experience. A local anesthetic can be replaced by another local anesthetic from the same group. However, there can be a significant difference in onset, duration, and success rate.

bNote: Chloroprocaine, mepivacaine, and lidocaine are routinely used with bicarbonate.

cDuration of anesthesia more predictable than duration of analgesia.

dLocal anesthetics for distal blocks should not contain epinephrine.

Systemic absorption of local anesthetics can produce central nervous system and cardiovascular toxicity. The rate and extent of absorption mainly depend on site of injection, total dose of local anesthetic, chemical properties of the local anesthetic, and addition of epinephrine. In general, body areas rich in vascular supply have more rapid and complete uptake, regardless of the type of local anesthetic. The rate of absorption is maximal for intercostals and decreases in the following order: intercostal, caudal, epidural, brachial plexus, sciatic, lumbar plexus, and femoral.

Central Nervous System Toxicity

Local anesthetics can cross the blood–brain barrier readily; toxic effects are related to the plasma level of the specific agent. The initial signs are usually excitatory, and include numbness of the tongue, lightheadedness, dizziness, visual disturbances, tinnitus, and disorientation. If unchecked, these symptoms progress to tonic–clonic convulsions and eventually to generalized central nervous system depression, respiratory depression, and respiratory arrest.

Cardiovascular System Toxicity

Initially, there is an increase in blood pressure and heart rate. With higher levels of local anesthetics, hypotension (direct vasodilatory effects on peripheral arterioles and negative inotropic action) and arrhythmias ensue, resulting in cardiac arrest.

Suggested Readings

Erlacher W, Schuschnig C, Koinig H, et al. Clonidine as adjuvant for mepivacaine, ropivacaine and bupivacaine in axillary, perivascular brachial plexus block. Can J Anaesth 2001;48:522–555.

Klein SM, Pietrobon R, Nielsen KC, et al. Peripheral nerve blockade with long-acting local anesthetics: a survey of the Society for Ambulatory Anesthesia. Anesth Analg 2002;94:71–76.

Litz RJ, Popp M, Stehr SN, Koch T. Successful resuscitation of a ropivacaine-induced asystole after axillary plexus block using lipid infusion. Aneasthesia 2006;61:800–801.

Mather LE, Chang DH. Cardiotoxicity with modern local anaesthetics: is there a safer choice? Drugs 2001;61:333–342.

Paqueron X, Boccara G, Bendahou M, et al. Brachial plexus nerve block exhibits prolonged duration in the elderly. Anesthesiology 2002;97:1245–1249.

Rosenblatt M, Abel M, Fischer G, Itzkovich Ch, Eisenkraft J. Successful use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacaine-related cardiac arrest. Anesthesiology 2006;105:217–218.

B. Drugs Added to Local Anesthetics

Aims of Coadministration

Various additives can be added to local anesthetics to accelerate the onset time, reduce the systemic absorption (thus the risk for LA-related toxicity), and prolong the duration of nerve block or pain relief.

The most commonly used additives for peripheral nerve blocks are vasoactive agents like epinephrine, clonidine, and opioids. Other additives are used for particular blocks, like hyaluronidase, which is typically used for ophthalmic blocks. Unfortunately, few properly designed and conducted studies have evaluated the usefulness of each additive, and we are still lacking definitive data to recommend or exclude additives for peripheral nerve blocks

Epinephrine

Site of Action: Local.

Mechanisms: Slowed blood absorption of the local anesthetic by epinephrine-induced vasoconstriction.

Main Effects: Prolonged duration of the block. Duration may be increased from 30% to 50%, depending on the potency of local anesthetics and the vasculature at the site of injection. The best effects are obtained with lidocaine and during intrapleural anesthesia. No effects were observed with ropivacaine.

Other Effects: Reduction of the inherent toxicity of local anesthetics. Peak plasma concentration may be reduced up to 50%.

Adverse Effects: Hemodynamic effects if massive blood absorption or intravascular injection. Tachycardia or arrhythmia indicates an inadvertent intravascular placement of the needle or catheter and necessitates the immediate cessation of local anesthetic injection.

Dose: 5 µg/mL (1/200,000).

Use: All peripheral blocks except those in the vicinity of extremities because of terminal arterial blood flow. For example, epinephrine is contraindicated in a penis block. It must be considered that because vasoconstrictors reduce the perfusion of vasa nervorum, they might potentially increase the risk for an ischemic nerve injury. For this reason the extensive use of vasoconstrictors is not recommended for continuous infusion, especially when using a continuous infusion rather than an intermittent bolus technique.

Clonidine

Clonidine is the only α2-agonist used in combination with local anesthetics. Its use is well documented.

Site of Action: Local, but also central after blood absorption from the nerve sheath.

Mechanisms: Weak local anesthetic action of the α2-agonist itself but possibility of synergistic interaction with local anesthetics. Effects may be due in part to a local pharmacokinetic mechanism.

Main Effects: Prolonged duration of anesthesia and analgesia that follows neural blockade, depending on the potency of local anesthetics, lesser effects being observed when added to ropivacaine and bupivacaine. Anesthesia may be prolonged by 30% to 50% with mepivacaine supplemented with 150 mg clonidine. Analgesia may be prolonged by 40% to 400% when clonidine is added.

Other Effects: Clonidine can extend the sensory block and improve its quality at the time of surgery.

Adverse Effects: Sedation is the main, and often the sole, adverse effect. This must be taken into consideration in a premedicated patient. Other effects include decreased blood pressure and slowed heart rate. Rarely, there is an abnormal ventilatory pattern.

Dose: The minimum dosage, which results in significant prolongation of anesthesia, is 0.5 µg/kg. Increasing the dose results in a greater number of adverse effects. The suggested dose for a single shot nerve block is 1 µg/kg. Clonidine has been also added to local anesthetic solution for continuous peripheral nerve blocks, with a reported reduction in the number of self-administered bolus doses on the first two postoperative days. However, the addition of 1 µg/mL clonidine for continuous femoral nerve block after knee joint replacement has also been demonstrated to produce persistent motor function impairment after 48 hours of infusion in 27% of patients compared with only 6% of cases in patients not receiving clonidine at all or receiving it only with the initial bolus. This potentiation of motor block effects of local anesthetics has also been reported during continuous epidural infusion, and must be considered if early mobilization is required to implement patient rehabilitation.

Use: All peripheral nerve blocks.

Opioids

Although opioid agents are known to exert their analgesic activity at a spinal and supraspinal level, there are biochemical and clinical evidences suggesting that opioids may also act at the level of peripheral nerves, due to the peripheral expression of opioid receptors activated by tissue stress and inflammation. Whether such an effect may improve clinical neural blockade and analgesia is debated. Inflammatory phenomena, history of chronic pain, and site of injection might account for conflicting results. However, at the current status of the art, there is no strong enough evidence supporting the extensive use of peripheral opioids as additives to local anesthetics.

Tramadol is a weak opioid receptor agonist; however, in contrast to other opioid agents it also has a significant effect on the reuptake of serotonin and norepinephrine. Moreover, it has been demonstrated to have a local anesthetic-like effect on peripheral nerves, potentially providing a synergistic effect when added to local anesthetics.

Site of Action: Central, but hypothesized also local.

Mechanisms: Hypothetical effect on axonal opioid receptors. Action on spinal cord either by diffusion or by centripetal axonal transport also has been invoked.

Main Effects: Analgesia lasting several hours, unrelated to the opioid dose injected.

Other Effects: Reduction of onset time of the block with the use of highly lipid soluble drugs.

Adverse Effects: Nausea and vomiting, some cases of pruritus.

Dose: The addition of 3 to 5 mg of morphine to the local anesthetic mixture has been reported to prolong the duration of analgesia up to 36 hours. The combination of 0.1 mg/kg of morphine and lidocaine injected locally can reduce by 50% the total dose of morphine required for postoperative analgesia.

Use: Documented only for brachial plexus blocks.

Alkalinization

All local anesthetics are weak bases, with a pKa ranging between 7.6 and 8.9; while most local anesthetic solutions commercially available are at low pH, ranging between 3 and 6. The addition of sodium bicarbonate is aimed at increasing the proportion of local anesthetic molecules not in cationic form, thus increasing the gradient of more lipophilic state of the molecule penetrating the phospholipidic layers of the nervous fibers membrane. This has been reported to accelerate the onset time of nerve block.

Site of Action: Local.

Mechanisms: Local anesthetics penetrate nerve cell membranes in their nonionized form and act intracellularly in their ionized form. Because local anesthetics are weak bases, addition of sodium bicarbonate increases their pH to the physiologic range, thus decreasing the ionized/nonionized ratio. This results in both an increased rate of penetration and a greater total mass of local anesthetic in the nerve.

Main Effects: There is a 30% to 50% reduction in onset time (i.e., approximately a 4-minute reduction with mepivacaine, 8 minutes with lidocaine, and 14 minutes with bupivacaine). The extent and quality of the block are improved.

Other Effects: Prolonged duration of analgesia has also been reported.

Adverse Effects: Unknown.

Dose: Theoretically, to adjust the pH of local anesthetic solutions to the physiologic range. This is unknown in clinical practice, which may account for many supportive trials being negative.

Use: All peripheral nerve blocks.

Neostigmine

Neostigmine is an acetylcholinesterase inhibitor that has been found after systemic or spinal administration to enhance analgesic effects of opioids or local anesthetics through activation of intrinsic ascending and descending cerebral cholinergic pathways. It has a possible peripheral analgesic effect after intraarticular injection.

Site of Action and Mechanisms: Hypothetical stimulation of acetylcholine receptors at the peripheral nerve level.

Main Effects: Not proved with 500 mg.

Adverse Effects: Gastrointestinal disorders with this dosage.

Verapamil

Verapamil is the only calcium blocker used in combination with local anesthetics to potentiate the channel-blocking activity of local anesthetic molecules.

Site of Action: Local, but also possibly central.

Mechanisms: Fast channel-blocking effects as local anesthetics.

Main Effects: 30% prolongation of sensory blockade with lidocaine with 2.5 mg verapamil.

Adverse Effects: Not reported with this dosage.

Dose: 2.5 mg.

Hyaluronidase

Site of Action: Local.

Mechanisms: Enzyme acting on hyaluronic acid, a component of several connective tissues. Hyaluronidase liquefies the interstitial barriers and increases the spread of local anesthetic solutions through tissue planes.

Main Effects: Reduction of onset time (not evaluated).

Adverse Effects: Rare cases of allergy.

Dose: Not clearly established, from 50 to 150 U.

Suggested Readings

Bernard JM, Macaire P. Dose-range effects of clonidine added to lidocaine for brachial plexus block. Anesthesiology 1997;87:277–284.

Bouaziz H, Paqueron X, Bur ML, et al. No enhancement of sensory and motor blockade by neostigmine added to mepivacaine axillary plexus block. Anesthesiology 1999;91:78–83.

Casati A, Vinciguerra F, Cappelleri G, et al. Adding clonidine to the induction bolus and postoperative infusion during continuous femoral nerve block delays recovery of motor function after total knee arthroplasty. Anesth Analg 2004;100:866–872.

Ilfield B, Morey TE, Enneking FK. Continuous infraclavicular perineural infusion with clonidine and ropivacaine compared with ropivacaine alone: a randomized, double-blinded, controlled study. Anesth Analg 2003;97:706–712.

Kapral S, Gollmann G, Walt B, et al. Tramadol added to mepivacaine prolongs the duration of an axillary brachial plexus blockade. Anesth Analg 1999;88:853–856.

Murphy DB, McCartney CJ, Chan VW. Novel analgesic adjuncts for brachial plexus block: a systematic review. Anesth Analg 2000;90:1122–1128.

Picard PR, Tramèr MR, McQuay HJ, et al. Analgesic efficacy of peripheral opioids (all except intra-articular): a qualitative systematic review of randomized controlled trials. Pain 1997;72:309–318.

Reuben SS, Reuben JP. Brachial plexus anesthesia with verapamil and/or morphine. Anesth Analg 2000;91:379–383.

Tetzlaff JE, Yoon HJ, Brems J, et al. Alkalinization of mepivacaine improves the quality of motor block associated with interscalene brachial plexus anesthesia for shoulder surgery. Reg Anesth 1995;20:128–132.

Watson D. Hyaluronidase. Br J Anaesth 1993;71:422–425.