Types: Structure and Function
Local anesthetics (LA) inhibit nerve function by blocking voltage-gated sodium channels in the nerve axons, thereby preventing an action potential. The agent penetrates the lipid membrane via its nonionized state and enters the nerve cell. Once inside, it dissociates into its charged form, allowing it to
bind to the sodium channel and block the movement of sodium ions. This in turn inhibits the action potential from initiating and inhibits the nerve’s ability to transmit an action potential.
FIGURE 6-11. The sural nerve. (A) Posterior view of a right ankle anatomic specimen. The sural nerve and lesser saphenous vein are identified and avoided during surgery. (B) Lateral view of an anatomic right ankle specimen demonstrating the course of the sural nerve. Note the proximity of the nerve to a calcaneal distraction pin. In addition, it is very near the subtalar portals.
These agents can be categorized according to their basic chemical structure, which determines their method of metabolism. The “ester” compounds are metabolized by plasma cholinesterase, whereas the “amide” compounds are metabolized in the liver. The two groups are also different in their allergic potential. The properties of these compounds that allow for varied clinical applications include their lipid solubility, protein binding, intrinsic vasodilator property, and the pH or pKa of the drug. Each medication has its own unique physiochemical profile in terms of potency, duration of action, and speed of onset of action. The potency of the anesthetic agent directly correlates with its lipid solubility. The duration of action of the agent is increased with more protein binding as less of the medication is available for metabolism. The intrinsic vasodilator activity of local anesthetics is due to their biphasic effect on vascular smooth muscle. A vasoconstriction effect occurs with lower concentrations, whereas at higher concentrations, local anesthetics function as vasodilators (as seen with nerve blocks). Thus, the agent with greater intrinsic vasodilator activity exhibits a shorter duration of action. Lastly, the speed of onset of the drug’s action is determined by its pH or pKa, which determines its ionization. When this value approximates the physiologic pH of the body, the onset of action of the drug is more rapid as the nonionized form easily crosses the nerve’s membrane allowing the ionized form to take action.6
Risks of Local Anesthetics
Risks associated with the use of local anesthetics for regional anesthesia include systemic toxicity (central nervous system [CNS] and cardiovascular). These physiologic effects are due to high blood levels of a local anesthetic. This may occur due to a direct intravascular injection or an overdose of a particular agent (cumulative effect of an excessive dosage). The potential for such toxicity is directly related to the intrinsic potency of the particular local anesthetic used.
Table 6-2. Local Anesthetics and Duration of Anesthesia
Duration of Surgical Anesthesia
Duration of Postoperative Analgesia
Bupivacaine 0.5% and 0.625%
Lidocaine/mepivacaine plus bupivacaine
Most toxic reactions to local anesthetics involve the CNS, as cardiovascular depression occurs at much higher blood levels of local anesthetic. The CNS changes encountered with excessive blood levels include light-headedness, dizziness, tinnitus, and nystagmus and may progress to confusion, slurred speech, and ultimately seizure activity (tonic-clonic). Several factors can contribute to CNS toxicity including the additive effect of combining different local anesthetics. Also, the rate of rise of the local anesthetic blood level can affect the degree of systemic and CNS toxicity. Adding epinephrine supplementation (not with ankle blocks) can provide advanced warning of an intravascular injection, as it prevents rapid absorption and high blood levels of anesthetic agents. A very rapid rise may lead to seizure activity, whereas a slow rise may produce such symptoms as irritability, restlessness, circumoral numbness, ringing in ears, metallic taste, and twitching of the eyelids and lips. Lastly, the acid-base status can markedly affect the degree of system toxicity. Acidosis decreases the convulsive threshold of various local anesthetics. Therefore, performing a PNB with a large volume of local anesthetics on a deeply sedated patient who is hypoventilating, therefore having increased pCO2 and becoming more acidotic, may increase the patient’s risk of systemic toxicity.
Toxic blood levels of local anesthetics affect the vasculature tone as well as cardiac contractility, rhythm, and conduction. The depressive effects of local anesthetics on the heart and vasculature may present as hypotension due to peripheral vasodilatation and diminished strength of cardiac contractions. Excessive toxicity can lead to bradycardia and subsequent cardiac arrest. The more potent anesthetics, such as bupivacaine, are more likely to induce these changes (especially with intravascular injections) due to their greater potency as calcium channel blockers. It is important to remember that in an anesthetized patient, the dominant manifestation of local anesthetic toxicity is myocardial depression, while in an awake patient, it is cardiac dysrhythmia.
The order of increasing toxicity is as follows: Chloroprocaine < Procaine < Prilocaine < Lidocaine < Mepivacaine < Ropivacaine < L-Bupivacaine < Bupivacaine.
Local Anesthetic Systemic Toxicity
The likelihood and severity of local anesthetic systemic toxicity (LAST) are multifactorial, involving several factors such as block specifics, total local anesthetic dose, patient risk factors including pre-existing comorbidities and current medications, detection, and treatment.
Sources of toxicity:
Progression of signs and symptoms:
Several patient-related factors should be considered when rather large doses of local anesthetics are used. In elderly, for example, there is decreased clearance of LA of multifactorial etiology, so the dose of local anesthetic should be reduced by 10% to 20% over the age of 70. In patients with renal dysfunction, the clearance of bupivacaine and ropivacaine is lower, and toxicity becomes more of a risk with prolonged infusions. If hepatic dysfunction is present, the dose does not need to be reduced for single-shot blocks. A lower dose is also advised if renal dysfunction is present as well. Patients with heart failure need no adjustment in dose, unless the heart failure is not controlled. One may want to avoid epinephrine-containing solutions, especially if hypokalemia is present. Pregnant patients also require a lower dose of LA, given the increased sensitivity of neuronal axons to neuronal blockade.
A reduction of dose should also be considered in patients with ischemic heart disease or cardiac conduction defects.
It should always be kept in mind that general anesthesia may impact the pharmacokinetics of local anesthetics, as well as their systemic effects.
Several safety steps should be considered to prevent LAST:
Incremental injection of 3 to 5 mL of local anesthetic.
Use of markers of intravascular injection.
The dose of local anesthetic should be individualized, block, and site specific.
The American Society of Regional Anesthesia (ASRA) released a practice advisory on LAST (Local Anesthetic Systemic Toxicity), including recommendations for prevention, diagnosis, and treatment of LAST.7
Local anesthetic toxicity—immediate treatment:
Call for help.
Stop injecting the local anesthetic.
ABC, including prompt airway management.
Control the seizures with benzodiazepines.
CPR if needed per ACLS protocol.
Consider lipid emulsion therapy at first signs of LAST.
20% lipid emulsion bolus of 1.5 mg/kg IV over 1 minute, followed by infusion at 0.25 mg/kg/min. Additional boluses may be given. Upper limit dose of the initial administration is 10 mg/kg.
Note that propofol is not a substitute for lipid emulsion therapy.
At least 12 hours of observation are recommended for any patient with significant LAST.
Measures to decrease the risk of LA toxicity:
Use of epinephrine as intravascular marker, when not contraindicated
Slow, gentle injection
Avoidance of high injection pressures
Constant monitoring of patient’s status and vitals
Careful selection of agent and volume
One must always remember that the classical LAST presentation may be absent, and atypical or unexpected presentations may also be encountered. A high level of vigilance and suspicion is warranted, especially in older patients who have additional risk factors for LAST.
While one would intuitively think that LA toxicity is more frequent with lower extremity (LE) blocks, given the large volumes of LA needed for combined blocks, this is not the case. There are few case reports of LA toxicity with LE blocks, much less than the upper extremity (UE), mainly because of anatomical considerations.
Certain medications may be used to enhance the efficacy of PNBs with local anesthetics. Regional blood flow analyses with these agents suggest that epinephrine is more effective than norepinephrine.8
Vasoconstrictor agents such as epinephrine, norepinephrine, and phenylephrine used in conjunction with local anesthetics may prolong their duration of action and quality of the block. However, these agents do decrease nerve blood flow as well, which may lead to an ischemic nerve injury, especially in those with a compromised vascular status, such as in patients with diabetes, pre-existing neuropathies, and peripheral vascular disease. The traditional wisdom mentioned in major textbooks is that the use of epinephrine in ankle blocks is not advised for potential further reduction of blood flow. However, a retrospective review of over 150 patients that received local anesthetics combined with epinephrine showed no complications in the foot or ankle.9
Using epinephrine as an adjuvant may therefore provide some beneficial effects, such as increase duration of anesthesia, decrease local anesthetic blood concentration, and decrease hemorrhage and hematoma formation.
The addition of sodium bicarbonate to a local anesthetic has been advocated to increase the speed of onset of the nerve blockade. Recent studies failed to confirm this effect, so the addition of bicarbonate to local anesthetic solutions that have freshly added epinephrine is not recommended.10
Even more, the addition of bicarbonate to bupivacaine, L-bupivacaine, and ropivacaine results in precipitation.