Bupivacaine

Article Author:
Fourutan Shafiei
Article Editor:
Javier Lopez
Updated:
12/2/2018 12:37:57 PM
PubMed Link:
Bupivacaine

Indications

Bupivacaine is a potent local anesthetic with unique characteristics from the amide group of local anesthetics which was first discovered in 1957. Local anesthetics are used in regional anesthesia, epidural anesthesia, spinal anesthesia, and local infiltration. Local anesthetics generally block the generation of action potential in nerve cells by increasing the threshold for electrical excitation. The progression of anesthesia is dependent on factors such as the diameter, degree of myelination, and conduction velocity of nerve fibers. In clinical practice, the order of loss of nerve function is as follows:[1][2]

  1. Pain
  2. Temperature
  3. Touch
  4. Proprioception
  5. Skeletal muscle tone

Mechanism of Action

All local anesthetics (LA) contain three structural components: an aromatic ring, a connecting group which is either an ester (procaine) or an amide (bupivacaine), and an ionizable amine group. All LAs have two chemical properties that determine their activity:

  1. Lipid solubility
  2. Ionization constant (pKa)

Lipid solubility determines potency, duration of action and plasma-protein binding of LAs. LAs enter nerve fibers as a neutral free base. Ionized forms and the cationic form blocks conduction by its interaction on the inner surface of Na+ channel. Moreover, LAs with lower pKa have a more rapid onset of action, meaning more of it exists in an uncharged form, which renders faster diffusion to the cytoplasmic side of Na+ channel.

Na+ channels are membrane proteins that propagate action potentials in axons, dendrites, and muscle tissue. They initiate and maintain membrane potential in specialized heart and brain cells. Depending on the tissue Na+, channels contain one larger alpha subunit and one or two smaller beta-subunits.

The alpha subunit, the site of ion conduction, and LA binding have four similar domains, each with six alpha-helical membrane-spanning segments. The external surface of the alpha-subunit is heavily glycosylated, which allows the channel to orient properly within the cytoplasmic membrane. In contrast to LAs, scorpion toxins and tetrodotoxin have binding sites on the extracellular surface of the Na+ channel.

Conduction of nerve impulses is through the generation of an action potential along an axon. Local anesthesia results when LAs bind Na+ channel and inhibit the Na+ permeability necessary for the action potential. LAs selectively inhibit the open form of voltage-gated Na+ channels. Na+ channel blockade results in the decrease or elimination of conduction in vascular smooth muscle, leading to relaxation. In the heart, this leads to decreased pacemaker activity and prolongation of the refractory period. This is unique to Bupivacaine due to its decreased rate of dissociation from blocked sodium channels which leads to prolongation of the maximal rate of depolarization (Vmax) and potential for ventricular arrhythmias. Also, LAs produce a dose-dependent myocardial depression and interference with Ca2+ signaling within the cardiac muscle because they also bind and inhibit cardiac voltage-gated-Ca2+ and K+ channels.

LAs also bind beta-adrenergic receptors and inhibit epinephrine-stimulated cAMP formation, which can explain the refractoriness of bupivacaine CV toxicity to standard resuscitation guidelines. In the central nervous system (CNS), LAs may cause increased excitability, followed by its depression.

Neuronal tissues have different susceptibility to LAs. Depolarizing currents in nerves move along nodes of Ranvier, and 2-3 nodes must be blocked to impair neuronal conduction completely. Smaller fibers have smaller intermodal distance and, therefore, blocked by LAs more quickly.[3]

Administration

Bupivacaine is offered in three different concentrations: 0.25%, 0.5%, and 0.75%.

It is administered by local infiltration (post-surgical analgesia), peripheral nerve blocks (dental or other minor surgical procedures, orthopedic surgery), spinal anesthesia (injected into the CSF to produce anesthesia for orthopedic surgery, abdominal surgery, or cesarean delivery), epidural anesthesia/analgesia for labor pain, and for caudal block (anesthesia and analgesia below the umbilicus, usually for pediatric surgery).[4]

Adverse Effects

The dose of bupivacaine depends on the procedure, the vascularity of the tissue, the area, the number of segments blocked, the depth or duration of anesthesia needed, and the physical condition of the patient. Bupivacaine may interact with ergot medications used for migraine headaches, blood thinners, antidepressants, or monoamine oxidase inhibitors. Immunologic reactions to LAs are rare. Allergic reactions to preservative-free amide-type LAs are rare and usually not reported. A true anaphylactic response appears more common with ester LAs or preservative/epinephrine-containing LA is often misdiagnosed as allergic reactions. Patients may also react to preservatives such as methylparaben, which is included with LAs.  Methemoglobinemia has been reported in association with benzocaine, but lidocaine and prilocaine have also been reported. O-toluidine, the liver metabolite of prilocaine, is a potent oxidizer of hemoglobin to methemoglobin. At low levels (1% to 3%), methemoglobinemia can be asymptomatic, but higher concentrations (10% to 40%) may accompany cyanosis, cutaneous discoloration (gray), tachypnea, dyspnea, exercise intolerance, fatigue, dizziness, syncope, and weakness.

Some more common adverse effects include nausea, vomiting, chills or shivering, headache, back pain, dizziness, sexual dysfunction, restlessness, anxiety, vertigo, tinnitus, blurry vision, tremors which may precede more severe adverse effects such as convulsions, myoclonic jerks, coma, and cardiovascular collapse.[2]

Contraindications

Contraindications include hypersensitivity to the drug or its components, hypersensitivity to amide anesthetics, infection at injection site, OB paracervical block, OB anesthesia using 0.75% concentration, intravenous regional anesthesia, and intra-articular continuous infusion. Use with caution in patients with hypersensitivity to sulfites, liver impairment (the liver clears amides), kidney impairment, impaired cardiac function, heart block, hypovolemia, hypotension, and elderly, debilitated, or acutely ill patients.[5]

Monitoring

Standard monitoring required during the administration of bupivacaine includes

  1. Continuous EKG
  2. SpO2
  3. Blood pressure.

Ask patients to report any numbness around the lips or mouth, metallic taste, ringing in their ears, tremors, and ominous feelings. If the patient reports any of these symptoms, administration of bupivacaine must stop immediately, and treatment as per guidelines must follow.[2]

Toxicity

Most local anesthetics produce similar signs and symptoms, but the ratio of neurotoxicity to cardiotoxicity may be different, with bupivacaine being the most cardiotoxic. The incidence of toxicity is rare: 1:1000 to 1:10,000. Be concerned for local anesthetic toxicity (LAST) with abnormal cardiovascular or neurological signs and symptoms.

The site at which LA is administered also increases the chance of toxicity.  IV injection is the most common reason for LA toxicity, and the toxic dose of bupivacaine is > 3mg/kg.

Most-to-Least toxic sites IV>Intercostal>Caudal>Epidural>Interfascial plane blocks of the abdominal wall (TAP)> Psoas compartment blocks>Sciatic blocks>Cervical plexus block>Brachial plexus block.

Pathophysiology

At therapeutic levels, LAs block voltage-gated Na-channels at alpha subunit inside the channel, preventing Na+ influx, preventing depolarization and action potential generation. At toxic levels, they affect cardiac Na+-channels and neurons in the brain, blocking K+, Ca2+ and NMDA receptors. Local anesthetics also interfere with cellular processes including oxidative phosphorylation, free fatty acid utilization, and cAMP production. Toxic levels of LAs on the heart lead to conduction irregularities, impaired cardiac contractility, and the loss of vascular tone secondary to extreme vasodilation.

Signs and Symptoms

Neurological

  • Early - perioral tingling, tinnitus, blurry vision, and tongue paresthesias, advances to CNS depression (slurred speech and drowsiness),
  • Late agitation, confusion, AMS, seizures. Depressive phase - coma and respiratory depression.

Cardiovascular

Hypertension and tachycardia; intermediate- myocardial depression and hypotension. Terminal - vasodilation, severe hypotension, dysrhythmias, conduction blocks, and asystole.

Hypercarbia

Lowers seizure threshold and increases cerebral blood flow, leading to more LA into the brain. Acidosis also impairs protein binding of LA and leads to a more free fraction in plasma which leads to more LA delivery to the brain.

Treatment

The first step is to call for help. Treatment is based on presenting symptoms. Treat seizures with GABA agonists. Treat convulsions with paralytics and airway management. Vasopressors may be indicated, although in some animal models they have been shown to promote CNS toxicity but do not hold because of the potential cardiovascular toxicity. Total cardiovascular collapse may be treated with CPR plus based on the source with 1.5 to 4 mL/kg bolus of 20% lipid solution followed by 0.25 to 0.5 mL/kg/min infusion for 10 to 60 minutes. For detailed, step-by-step treatment guidelines please refer to Treatment Guidelines for LAST from the American Society of Regional Anesthesia (ASRA).[2]