Bupivacaine

Article Author:
Fourutan Shafiei
Article Author:
Russell McAllister
Article Editor:
Javier Lopez
Updated:
6/22/2020 10:40:01 AM
PubMed Link:
Bupivacaine

Indications

Bupivacaine is a potent local anesthetic with unique characteristics from the amide group of local anesthetics, 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 an 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 a 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 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 local anesthetics. Local anesthetics enter nerve fibers as a neutral free base. Ionized forms and the cationic form blocks conduction by its interaction on the inner surface of the 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 the 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 local anesthetic 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 local anesthetics, 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. Local anesthetics 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 action 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.

Local anesthetics 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), local anesthetics may cause increased excitability, followed by its depression.

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

Administration

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

Administration is 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 a caudal block (anesthesia and analgesia below the umbilicus, usually for pediatric surgery).[4]

Adjuvants are often added to local anesthetics for nerve blocks with the goal of prolonging the anesthetic effects when compared to LA alone.  Alpha 2 agonists such as clonidine or dexmedetomidine combined with the LA have shown to increase the duration of anesthesia significantly.  Additionally, dexamethasone, when mixed with the local anesthetic for nerve blocks, has also been shown to increase the duration of anesthesia, although the mechanism is unclear as to whether it is a direct neural effect or simply the systemic effect of the steroid anti-inflammatory processes.  Magnesium, with its N-methyl D-aspartate receptor antagonist effects, has also been associated with prolonged duration of action of local anesthetics for nerve blocks.  Studies are ongoing evaluating the effects of these and other potential adjuvants to LAs to prolong effectiveness while minimizing the risk of toxicity.[5]

In the last decade, it has been shown that ultrasound-guided nerve blocks are associated with a decreased risk of local anesthetic toxicity.  Presumably, visualization of the nerve and surrounding structures decreases the likelihood of injection into a vascular structure and increases the early recognition of this occurrence, thereby lessening the possibility of reaching toxic levels of bupivacaine in the bloodstream.[6]

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 local anesthetics are rare. Allergic reactions to preservative-free amide-type local anesthetics are rare and usually not reported. A true anaphylactic response appears more common with ester local anesthetics or preservative/epinephrine-containing local anesthetics often gets misdiagnosed as allergic reactions. Patients may also react to preservatives such as methylparaben, which are included with local anesthetics. 

Methemoglobinemia is typically associated with benzocaine or prilocaine; however, case reports exist implicating bupivacaine in rare instances.  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 the injection site, obstetric paracervical block, obstetric 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.[7]

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, the 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 to 1000 to 1 to 10000. Be concerned for local anesthetic toxicity (LAST) with abnormal cardiovascular or neurological signs and symptoms.

The site of administration of local anesthetic also influences the risk of toxicity.  Unintended direct intravenous injection or rapid vascular uptake of the drug is the most common reason for bupivacaine toxicity, which has an upper limit of 2.5 to 3.5 mg/kg upper limit of dosing. Depending on the vascularity of the injection site and the technique, toxicity of the medication can occur if administering the upper limit of the dosing recommendations.  Signs and symptoms of toxicity may occur rapidly or be delayed.  

Rarely, patients can exhibit toxicity to bupivacaine in doses much lower than the suggested upper limits of dosing. This toxicity appears to be due to a rare condition related to l-carnitine deficiency.  Patients affected may exhibit cardiac toxicity at doses as low as 1.1 mg kg of bupivacaine injected cutaneously.  Case reports exist describing these cases of low dose toxicity in patients later discovered to be deficient in l-carnitine. A rat study demonstrated this model and found that the administration of supplemental l-carnitine could reverse this effect.[8]

Most-to-Least Toxic Sites Intravenous>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, local anesthetics 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 local anesthetics 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

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

Treatment

Treatment of bupivacaine toxicity has long been challenging due to its profound neurologic and cardiac toxicity. Previously, treatment had been supportive, with standard cardiopulmonary resuscitation, airway management, and seizure control with quick-acting GABA agonists such as midazolam. Because of the long duration of action for bupivacaine, toxicity was especially problematic. In centers where cardiopulmonary bypass was readily available, it was used to support the toxic patient until the drug was adequately metabolized and cleared, which may take hours. In the early 2000s, landmark research by Guy Weinberg revealed that lipid emulsion, such as the type that serves as the carrier for total parenteral nutrition formulations, was effective in rescuing laboratory animals from bupivacaine toxicity. The profound results in animals (mice and dogs) led to several case reports where lipid emulsion was used as a last resort in human patients with profound cardiovascular collapse following nerve blocks with long-acting local anesthetics such as bupivacaine and ropivacaine.  Over the following 15 years, the treatment with lipid emulsion became widely accepted as effective and was adopted by the American Society of Regional Anesthesia as the standard for treatment of local anesthetic systemic toxicity (LAST) and has been adopted into their treatment algorithm. Once only used as a last resort treatment, it is now widely used as a first-line treatment for these patients. Facilities that administer local anesthetics should have lipid emulsion readily available for emergencies. Interestingly, high dose epinephrine has shown associations with decreased effectiveness of lipid emulsion in the treatment of LAST. This evidence further emphasizes the importance of early treatment with lipid emulsion when LAST is suspected. Detailed treatment algorithms are available through the American Society of Regional Anesthesia's website.[9]  The current dosing recommendations for lipid emulsion 20% are as follows:

For a patient greater than 70 kg, bolus 100 mL of lipid emulsion 20% rapidly over 2 to 3 minutes and then infuse 200-250 mL over the next 15 to 20 minutes. Redosing may be necessary up to a maximum dose of 12 mL/kg.

For a patient of less than 70 kg, bolus 1.5 mL/kg lipid emulsion 20% rapidly over 2 to 3 minutes, followed by an infusion of 0.25 mL/kg/min for ideal body weight to an upper limit of 12 mL/kg.

A cardiopulmonary bypass should also still be considered early in case other treatments are ineffective.  

Enhancing Healthcare Team Outcomes

Bupivacaine is administered to patients by many healthcare professionals, including the surgeon, anesthesiologist, pain specialist, emergency department physician, and nurse practitioner. However, all healthcare workers who do administer the drug must know its potential side effects and toxicity.

Resuscitative equipment must be in the room at the time of the injection, and surgical nurses must be familiar with the proper use of this equipment in an emergency. The most common reason for a complication is an injection of the drug into the artery or vein, which can result in adverse cardiac and CNS effects.[10][11]

Pharmacists can be involved in preparing the agents and verifying proper dosing and administration, working with the anesthesiologist or nurse anesthetist. They can also assist in cases of toxicity with the needed drugs to address toxic states.

Bupivacaine use requires an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level 5]


References

[1] Shah J,Votta-Velis EG,Borgeat A, New local anesthetics. Best practice     [PubMed PMID: 30322458]
[2] Wolfe RC,Spillars A, Local Anesthetic Systemic Toxicity: Reviewing Updates From the American Society of Regional Anesthesia and Pain Medicine Practice Advisory. Journal of perianesthesia nursing : official journal of the American Society of PeriAnesthesia Nurses. 2018 Dec     [PubMed PMID: 30449428]
[3] Li J,Duan R,Zhang Y,Zhao X,Cheng Y,Chen Y,Yuan J,Li H,Zhang J,Chu L,Xia D,Zhao S, Beta-adrenergic activation induces cardiac collapse by aggravating cardiomyocyte contractile dysfunction in bupivacaine intoxication. PloS one. 2018     [PubMed PMID: 30273351]
[4] Iskander A,Gan TJ, Novel analgesics in ambulatory surgical patients. Current opinion in anaesthesiology. 2018 Dec     [PubMed PMID: 30346316]
[5] Prabhakar A,Lambert T,Kaye RJ,Gaignard SM,Ragusa J,Wheat S,Moll V,Cornett EM,Urman RD,Kaye AD, Adjuvants in clinical regional anesthesia practice: A comprehensive review. Best practice     [PubMed PMID: 31791560]
[6] Barrington MJ,Uda Y, Did ultrasound fulfill the promise of safety in regional anesthesia? Current opinion in anaesthesiology. 2018 Oct;     [PubMed PMID: 30004951]
[7] [Disputable issues of Malamed's "Handbook of local anesthesia" (2004)]., Petrikas AZh,Ol'khovskaia EB,Medvedev DV,Diubań≠lo MV,, Stomatologiia, 2013     [PubMed PMID: 23715461]
[8] Wong GK,Pehora C,Crawford MW, L-carnitine reduces susceptibility to bupivacaine-induced cardiotoxicity: an experimental study in rats. Canadian journal of anaesthesia = Journal canadien d'anesthesie. 2017 Mar;     [PubMed PMID: 28032304]
[9] Neal JM,Woodward CM,Harrison TK, The American Society of Regional Anesthesia and Pain Medicine Checklist for Managing Local Anesthetic Systemic Toxicity: 2017 Version. Regional anesthesia and pain medicine. 2018 Feb;     [PubMed PMID: 29356775]
[10] Teunkens A,Vermeulen K,Peters M,Fieuws S,Van de Velde M,Rex S, Bupivacaine infiltration in children for postoperative analgesia after tonsillectomy: A randomised controlled trial. European journal of anaesthesiology. 2019 Mar;     [PubMed PMID: 30640245]
[11] Hussain N,McCartney CJL,Neal JM,Chippor J,Banfield L,Abdallah FW, Local anaesthetic-induced myotoxicity in regional anaesthesia: a systematic review and empirical analysis. British journal of anaesthesia. 2018 Oct;     [PubMed PMID: 30236244]