Continuing Education Activity

Chloroprocaine is an ester class local anesthetic and is indicated for neuraxial anesthesia (caudal, epidural, and spinal) and peripheral nerve blocks and obstetric anesthesia (pudendal and paracervical blocks). Due to its short duration, it has been used in test doses to evaluate the function of peripheral nerve and epidural catheters. This activity reviews the mechanism of action, adverse event profile, toxicity, dosing, pharmacodynamics, and monitoring of chloroprocaine, pertinent for interprofessional team members where patient care requires local anesthesia that would be met using chloroprocaine.

Objectives:

• Identify the approved and off-label indications for chloroprocaine.
• Summarize the mechanism of action of chloroprocaine.
• Outline the necessary monitoring of chloroprocaine.
• Describe the importance of interprofessional team members to improve patient outcomes in patients receiving chloroprocaine for local anesthesia.

Indications

Chloroprocaine is an ester class local anesthetic with labeled indications to provide anesthesia through infiltration, peripheral nerve, epidural, and caudal block. Due to its low potential for systemic toxicity, chloroprocaine has been used to identify inadvertent intravascular epidural catheter insertion in pregnant and non-pregnant adults.[1]

The most common application for chloroprocaine is the obstetric setting, where it is used to provide fast onset epidural anesthesia when urgent or emergent cesarean delivery is indicated.[2][3] Large doses of chloroprocaine can be administered in this setting because of the low potential for maternal and fetal toxicity.[4]

Reports of adhesive arachnoiditis, cauda equina syndrome, anterior spinal artery syndrome, and other non-specified forms of permanent neurologic injury after intrathecal chloroprocaine administration were reported in the 1980s.[5][6][7][8] Published cases reporting permanent neurologic injury were generally associated with inadvertent intrathecal injection of an epidural dose, which would result in a significant overdose.[6][8] Generally speaking, an equivalent spinal block can be achieved with 10% of the epidural dose. Furthermore, studies showed that the chloroprocaine preservatives sodium bisulfite and disodium ethylenediaminetetraacetate (EDTA) could cause localized neurodegenerative changes in spinal nerve roots.[9][10] This limited enthusiasm for the application of chloroprocaine in spinal anesthesia until recently. The United States Food and Drug Administration recently approved a preservative-free formulation of chloroprocaine to provide spinal anesthesia for adults undergoing short-duration lower extremity and abdominal surgery.[11]

Mechanism of Action

Chloroprocaine causes reversible nerve conduction blockade by decreasing nerve membrane permeability to sodium.[12] Like other local anesthetics, chloroprocaine binds to a specific region of the alpha subunit on the cytoplasmic region to inhibit voltage-gated sodium channels. This binding activity increases the threshold for excitation in the nerve and slows nerve impulse propagation.[13] 

All local anesthetics exhibit differential blockade—the observation that nerve fibers associated with different functions have dissimilar sensitivity to the sodium channel blocking properties of local anesthetics.[14] A differential blockade is most commonly associated with spinal anesthesia, though it can be observed with epidural anesthesia and peripheral nerve blocks.  Nerve conduction through sympathetic nerves is blocked by the lowest concentration of chloroprocaine.  Nerves responsible for the reception of pain, temperature, light touch, pressure, and proprioception are blocked by the next lowest concentration of chloroprocaine.  Nerve fibers responsible for motor function are the most resistant and require the highest concentration of chloroprocaine for inhibition of nerve transmission.[15]

In general, the speed of onset for a local anesthetic is determined by its pKa (dissociation constant)—the pH at which half the drug is ionized (protonated) and half the drug is nonionized (uncharged).[13] Local anesthetics are stored in water-based solutions. Local anesthetics must be in ionized form to be stable in water-based solutions.  However, only the nonionized form of the local anesthetic can cross the nerve lipid membrane and block the sodium channel. All local anesthetics, including chloroprocaine, are weak bases (pKa > 7.0) with a pKa above physiologic pH (7.4).[14] Consequently, lower pKa is associated with a greater proportion of nonionized drugs, which typically equates to faster onset of action.[12] 

Chloroprocaine is an exception to this rule. Chloroprocaine has a pKa (8.7) greater than lidocaine, ropivacaine, bupivacaine, and mepivacaine, yet it can provide faster onset epidural anesthesia.[14] Chloroprocaine can provide fast onset anesthesia because it has a very low risk for systemic toxicity (it is rapidly metabolized by pseudocholinesterase) and can be administered in high doses, which creates a large diffusion gradient to drive quick onset. 

The nerve membrane is heavily occupied by lipids. Accordingly, more lipophilic substances cross the nerve membrane more easily, which provides more molecules to block nerve conduction.  In this manner, lipid solubility is one of the main determinants of local anesthetic potency.[14] The partition coefficient measures the distribution of substances between lipid and hydrophilic liquids. Chloroprocaine has one of the lowest partition coefficients (low lipophilicity) and has low potency relative to other local anesthetics.[14] 

Local anesthetics that exhibit higher degrees of plasma protein binding generally have a longer duration of action.  This is because protein binding in plasma can be used as a surrogate for local anesthetic affinity for protein binding in the sodium channel.[14] Highly protein-bound molecules such as bupivacaine exhibit a longer duration of action than lesser protein-bound molecules such as lidocaine. Chloroprocaine has the lowest protein binding of all clinically used local anesthetics and is amongst the shortest in duration of action.[14]

Local anesthetics are not specific for peripheral nerves; nerves in the central nervous system and cardiac conduction system may also be blocked.  Because of this, severe symptoms involving the central nervous and cardiovascular system may result when large doses of local anesthetic are injected—a syndrome commonly referred to as local anesthetic systemic toxicity (LAST).

Administration

Chloroprocaine is supplied as a 1%, 2%, and 3% solution. The spinal formation is 1% and preservative-free. Some of the solutions indicated for infiltration, epidural, and peripheral nerve block contain the preservatives methylparaben and disodium ethylenediaminetetraacetate (EDTA).

The maximum recommended chloroprocaine dose for infiltration, or peripheral nerve block is 11 mg/kg when chloroprocaine is administered alone, not to exceed 800 mg.[4] The maximum recommended chloroprocaine dose for infiltration, or peripheral nerve block is 14 mg/kg when chloroprocaine is co-administered with 1:200,000 epinephrine solution, not to exceed 1000 mg. Epinephrine allows for the administration of a higher dose because of the vasoconstriction that it causes, which decreases vascular uptake resulting in a lower peak plasma concentration.[16] 

The 3% chloroprocaine solution is typically used in lumbar epidural catheters to facilitate urgent or emergent cesarean delivery. Because chloroprocaine is used in the obstetric setting to facilitate quick onset anesthesia, the 3% solution is always used.  A volume of 15 to 25 mL is usually sufficient to obtain a T4 dermatome level—the level required to achieve a painless cesarean delivery. Since epidural anesthesia in the non-obstetric setting is often not as urgent, both 2% and 3% chloroprocaine are used.  Similar volumes are used in the non-obstetric population. A repeat dose of epidural chloroprocaine can be administered every 45 minutes to continue anesthesia; recovery following epidural block with chloroprocaine takes 30 to 60 minutes.[17]

The recommended dose of 1% intrathecal chloroprocaine in the non-obstetric population is 50 mg. This has been shown to produce a reliable and dense block to the T10 dermatome. Epinephrine should not be administered with spinal chloroprocaine as it has been associated with the following flu-like symptoms: malaise, myalgias, arthralgias, fever, nasal congestion, and loss of appetite.[18] Fentanyl may prolong spinal block with chloroprocaine without adversely impacting time to discharge.[19]

Adverse Effects

The most common adverse effect is pain related to the procedural injection of chloroprocaine. The next most common adverse effects are related to spinal, epidural, and caudal anesthesia: hypotension, bradycardia, nausea, and headache. 

Similar to other local anesthetics, if too much chloroprocaine is administered into the epidural or intrathecal space, a high block may occur. The most common scenario is an accidental intrathecal injection during epidural placement.  If the block is higher than the T1 dermatome, the cardiac accelerator fibers will be blocked, and bradycardia will ensue. This will usually be accompanied by hypotension, nausea, significant patient anxiety, and akathisia. If the block continues to rise, brainstem dysfunction may occur with associated loss of consciousness and apnea—this constellation of symptoms is commonly referred to as a “total spinal.”[20] Patients with a total spinal will have fixed, dilated pupils.

One case of cauda equina syndrome has been described after an appropriate dose of preservative-free intrathecal chloroprocaine. The patient developed urinary retention, severe lower extremity burning pain, leg weakness, and loss of sensation in the buttock and bilateral thighs. The patient’s symptoms resolved over 5 to 6 weeks.[21]

Anaphylaxis to local anesthetics is very rare. Ester local anesthetics, such as chloroprocaine, may have a higher incidence of allergic reactions due to one of their metabolites, para-aminobenzoic acid (PABA), which is structurally similar to methylparaben.[22]

Contraindications

Chloroprocaine is contraindicated in patients with a known allergy to para-aminobenzoic acid (PABA). 

Chloroprocaine is pregnancy category C. Studies involving pregnant animals have not been conducted.  Despite the category C classification, chloroprocaine is used regularly on labor and delivery units throughout the world.  Low concentrations of chloroprocaine and only trace amounts of its byproducts (2-chloro-aminobenzoic acid and 2-dimethylaminoethanol) have been found in umbilical arterial or venous plasma after properly administered paracervical blocks (the rate of systemic absorption of local anesthetics increases paracervical > epidural > IM > spinal).[23] Unlike other local anesthetics that cross the placenta, chloroprocaine’s rapid metabolism by pseudocholinesterase minimizes the amount that reaches the placenta. Additionally, chloroprocaine is supplied with a pKa of 8.7 and does not participate in ion trapping, a phenomenon in which molecules become protonated in the acidic fetal environment and are unable to cross the placenta back to the maternal circulation.[24] For these reasons, some clinicians have argued that chloroprocaine is the best local anesthetic to administer when there is fetal compromise and likely acidosis. 

It is unknown how much chloroprocaine is excreted into breast milk, but based on the low amounts of other local anesthetics, it is not thought to cause infant toxicity.[25] Maternal pseudocholinesterase rapidly metabolizes chloroprocaine and greatly diminishes the opportunity for chloroprocaine to enter the breastmilk. Infant pseudocholinesterase activity is very similar to maternal activity. Thus, any orally absorbed chloroprocaine would be rapidly metabolized in the infant, making toxicity quite unlikely. For this reason, chloroprocaine can be used to provide epidural, spinal, caudal, peripheral nerve, and infiltrative anesthesia in lactating women. 

Chloroprocaine should be used with caution in patients with end-stage liver disease as it is metabolized by pseudocholinesterase, which is produced in the liver. Somnolence and a prolonged epidural block have been described in a parturient with pseudocholinesterase deficiency.[26] Pseudocholinesterase activity can be reduced in the setting of severe preeclampsia.[27] Patients with neuromuscular diseases such as myasthenia gravis may exhibit increased sensitivity to chloroprocaine and a prolonged duration of action. 

Dosing for pediatric patients younger than four years old has not been established.

Monitoring

According to the American Society of Anesthesiologists (ASA), oxygenation, ventilation, and circulation should be continuously monitored during the performance of a regional anesthetic. The patient's condition may rapidly deteriorate with the provision of any type of anesthesia. Accordingly, qualified anesthesia personnel should be continuously present and prepared to escalate care should untoward clinical events occur.

During the performance of a block with chloroprocaine, oxygenation must be continuously assessed. The pulse oximeter is the most commonly used method to quantitatively assess the adequacy of oxygenation. 

During the performance of a regional block with minimal or no sedation, the adequacy of ventilation can be assessed by observation of chest excursion, mask fogging, and auscultation of breath sounds.  In July 2011, the ASA changed its recommendation to assess ventilation during moderate or deep sedation.[28] According to the ASA Standards for Basic Monitoring, ventilation should be assessed via measurement of exhaled carbon dioxide whenever a regional block is performed under moderate or deep sedation. 

Circulation should be continuously evaluated during the performance of a block with chloroprocaine. The electrical activity of the heart should be continuously assessed with an electrocardiogram. In addition, arterial blood pressure and heart rate should be monitored at 5-minute intervals or more frequently. 

The temperature should be assessed whenever clinically meaningful changes in body temperature are expected. Due to the short duration of procedures that involve chloroprocaine administration, temperature monitoring is usually not required while blocks are being performed. 

Toxicity

Local anesthetic systemic toxicity (LAST) refers to local anesthetics reaching toxic plasma levels. Initial signs of LAST are tinnitus, perioral numbness, and metallic taste. Classically, LAST progresses from central nervous system excitation (anxiety, muscle twitching, seizures) to depression (sleepiness, loss of consciousness, and respiratory depression) followed by cardiac excitation (tachycardia, hypertension) and finally depression (bradycardia, hypotension, arrhythmias, asystole).[29][30][31] However, the classic presentation is not always seen, and initial symptoms can be quite delayed.[29][32][33]

Chloroprocaine doses greater than 11 mg/kg may cause LAST. Please note that LAST has been reported with local anesthetic doses below the maximum recommended dose.[34] Due to its rapid metabolism, the incidence of LAST with chloroprocaine is extremely low. Most case reports of LAST involve administering local anesthetics with a much longer duration of action than chloroprocaine.[29][32] Self-limited 30-second wide complex bradycardia and 40-second self-limited seizure activity have been described after chloroprocaine administration to infants.[35][36][35] Dizziness, tinnitus, metallic taste, nausea, and narrow complex bradycardia have been described in adult patients undergoing intravenous regional anesthesia with chloroprocaine.[37] No long-term morbidity or mortality has been described after chloroprocaine administration.[35][36][37]

Careful attention to the prevention of overdose is necessary, with monitoring of the cardiovascular system and level of consciousness following each injection. If overdose is suspected, full hemodynamic support may be required. Benzodiazepines are the preferred treatment for seizures. Airway management for local anesthetic toxicity may range from supplemental oxygen to assisted ventilation to initiation of invasive airway devices and positive pressure ventilation. 

Critical differences in local anesthetic-induced cardiac arrest treatment include reduced doses of epinephrine (<1mcg/kg) and avoidance of vasopressin, calcium channel blocks, beta-blockers, or other local anesthetics. Dosing is 100 ml (or 1.5ml/kg for patients less than 70kg) 20% lipid emulsion given as a bolus followed by infusion is the treatment of choice for LAST.[38]

Enhancing Healthcare Team Outcomes

Bupivacaine is the most commonly used local anesthetic for spinal anesthesia. Bupivacaine has a long history of safe use, a low incidence of transient neurologic symptoms (post-spinal temporary radiating pain down the buttock and thighs), and it produces a reliable block.[39] The downside of bupivacaine is its long duration of action, up to 240 to 380 minutes.[40] Spinal chloroprocaine is an intriguing alternative to bupivacaine for short procedures (less than 60 minutes). The incidence of transient neurologic symptoms with spinal chloroprocaine is less than spinal lidocaine and equivalent to spinal bupivacaine.[19][41] Spinal chloroprocaine facilitates a shorter time to resolution of motor block, resolution of sensory block, first micturition, first ambulation, and discharge readiness, compared to bupivacaine and lidocaine.[17][40][42][43][44][45][46] In a randomized trial that included 50 patients having knee arthroscopy, spinal chloroprocaine was associated with lower costs than general anesthesia.[47] Multiple outcome studies involving spinal chloroprocaine are currently underway. Extrapolation of current studies involving spinal chloroprocaine suggests spinal chloroprocaine will become more common over the next decade.

Intraperitoneal chloroprocaine has been used off-label to provide adjunctive anesthesia for parturients undergoing cesarean delivery under the neuraxial block. In one case series, 32 patients were administered intraperitoneal chloroprocaine as part of a multimodal approach to avoiding general anesthesia when there was an imperfect neuraxial blockade.[48] Despite patients being administered a mean dose of 11.8 mg/kg, no clinical signs of local anesthetic toxicity were observed.

Epidural chloroprocaine is commonly used in the obstetric setting to provide rapid onset anesthesia for emergent cesarean delivery when an epidural catheter is in place. Chloroprocaine can be rapidly administered in large doses to provide rapid onset anesthesia without risking maternal or fetal systemic toxicity. The half-life of chloroprocaine in maternal and fetal plasma is 11.2 seconds and 15.4 seconds, respectively.[4] Due to its rapid metabolism, toxic concentrations of chloroprocaine are difficult to achieve.

While LAST is quite unlikely with chloroprocaine due to its rapid metabolism, vigilance for signs and symptoms of LAST is always recommended. Management of chloroprocaine-related toxicity (LAST) includes prompt recognition of the signs and symptoms and an interprofessional team to manage the potential consequences. LAST is an emergency condition that requires the full attention of nurses, technicians, and clinicians to maintain the airway and treat neurologic and cardiac complications.