When 2-chloroprocaine was first introduced in 1951, Foldes and McNall (1) described its use in 214 spinal anesthetics and reported no cases of neurotoxicity. It was never used extensively for spinal anesthesia, possibly because of the concurrent availability and widespread acceptance of lidocaine. Furthermore, by 1954, the only solutions of 2- chloroprocaine commercially available contained methylparaben, a preservative, or sodium bisulfite, an antioxidant, making them inappropriate for intrathecal injection (2). It has been used extensively for epidural anesthesia, particularly in obstetrics. In fact, 2- chloroprocaine was advocated as the epidural drug of choice for obstetrics because of its small potential for systemic toxicity to mother or fetus (3). In the 1980s, 8 patients were reported to have persistent neurological deficits after epidural anesthesia with 2-chloroprocaine. Four of these eight patients are known to have received unintentional subarachnoid injection of large volumes of bisulfite-containing 2-chloroprocaine (Nesacaine CE, Astra USA, Wilmington, DE) resulting in “total spinals”(4–6). Subsequent laboratory studies have shown that persistent neurologic deficits are associated with sodium bisulfite at low pH (<5.0) and that 2-chloroprocaine alone at pH = 3.2 or with bisulfite at pH = 7.2 did not produce irreversible neurologic deficits (7,8). Preservative-free solutions of 2-chloroprocaine appropriate for intrathecal injection are now available in 2% and 3% concentrations (Nesacaine-MPF, Astra USA; 2-chloroprocaine, Bedford Laboratories, Bedford OH).
Subarachnoid lidocaine is popular for spinal anesthesia because of its predictable duration and dense sensory and motor blockade. However, its use is associated with a syndrome of musculoskeletal pain radiating to the buttocks or lower extremities, commonly known as transient neurologic symptoms (TNS). Symptoms usually begin 6- 36 h after the spinal anesthetic and last 1–7 days. Pain is often described as cramping, aching, or lancinating and in some cases is quite severe (9). There are no persistent neurologic deficits. It is generally self-limited and responds well to nonsteroidal antiinflammatory drugs (NSAIDS). Although not life-threatening, TNS is an undesirable side effect that can negatively impact a patient’s functional status after surgery as well as their satisfaction with regional anesthesia. TNS occurs more frequently with lidocaine spinal anesthesia than with other local anesthetics, and has led many practitioners to abandon the use of lidocaine for spinal anesthesia (10).
We speculate that preservative-free 2-chloroprocaine may compare favorably with lidocaine for use in outpatient spinal anesthesia. This randomized, double-blinded crossover study was designed to compare spinal 2-chloroprocaine and lidocaine in volunteers using end-points of interest in outpatient anesthesia.
After IRB approval and written informed consent were obtained, 8 healthy volunteers were enrolled. Although 2-chloroprocaine has been approved by the Food and Drug Administration, it is not specifically indicated for use in spinal anesthesia. Its use for spinal anesthesia is thus considered “off-label.” All current manufacturers of 2-chloroprocaine distinctly label the product “Not for Spinal Anesthesia.” All subjects in this study were made aware of this information, which was also included within their written informed consent. Prior studies suggest 2-chloroprocaine has a similar anesthetic profile to lidocaine at a 45-mg dose (3 mL of 3% preservative-free 2-chloroprocaine) (11). All subjects had fasted for 6 h and received no sedatives during the study. Before subarachnoid block, a 20-gauge peripheral IV line was placed and an IV bolus of lactated Ringer’s solution (6 mL/kg) was administered, followed by an infusion of 8 mL · kg−1 · h−1 for the first hour and 2 mL · kg−1 · h−1 thereafter. A random number generator was used to determine order of drug administration. Each volunteer received 2 spinal anesthetics separated by at least 48 h, 1 with 2 mL plain, preservative-free 2% 2-chloroprocaine (40 mg; Nesacaine MPF, Astra USA) and the other with 2 mL preservative-free 2% lidocaine (40 mg, Abbott Laboratories, North Chicago, IL).
Spinal anesthesia was administered with the volunteers in the left lateral decubitus position. Under sterile conditions, and after local infiltration of the skin with 1% lidocaine, the subarachnoid space was entered at the L2–3 interspace via the midline approach using a 20-gauge introducer and a 24-gauge Sprotte needle. With the spinal needle orifice facing cephalad, 0.2 mL of the cerebrospinal fluid was aspirated, followed by injection of the study solution at a rate of 0.25 mL/s. After drug administration, a second 0.2-mL aspiration and reinjection of cerebrospinal fluid was used to confirm intrathecal injection. Subjects were immediately laid supine for the remainder of the study. Vital signs were monitored with continuous pulse oximetry, continuous electrocardiogram, and intermittent noninvasive blood pressure. Vasoactive drugs were administered only if symptoms of hypotension or bradycardia developed.
Bilateral sensory block to pinprick was tested by a blinded assessor in a cephalad to-caudad direction with a disposable dermatome tester every 5 min after injection for the first 60 min, then at 10-min intervals until complete resolution of sensory anesthesia. The right C5-6 dermatome was used as an unblocked reference point. Tolerance to transcutaneous electrical stimulation (TES) was determined at 6 common surgical sites: at the lateral ankle (S1) bilaterally, at the medial knee (L3) bilaterally, at the pubis midline (T12), and at the umbilicus midline (T10). TES was performed with a peripheral nerve stimulator (Model NS252; Fisher & Paykel, Auckland, New Zealand) using 50 Hz tetanus for 5 s initially at 10 mA and then with increasing increments of 10 mA to a maximum of 60 mA. This maximum limit was chosen because previous studies have shown TES at 60 mA to be equivalent to the intensity of stimulation caused by surgical incision (12). Testing began in a systematic cephalad-to-caudad order at 4 min after injection and continued at 10-min intervals until the subject could no longer tolerate 60 mA on 2 successive tests. If the subject was never able to tolerate 60 mA, the testing was terminated at 34 min.
Thirty minutes after injection, duration of the tolerance to left thigh tourniquet was assessed using a 34-inch pneumatic cuff that was inflated to 300 mm Hg after exsanguination by gravity. This is similar to the tourniquet application used in lower extremity orthopedic procedures at our institution. The subjects were instructed to request deflation of the tourniquet when the discomfort level reached a pain score of 5 on a 10-point scale or at a maximum time limit of 120 min.
Motor block of the abdominal and lower extremity muscles was assessed using electromyography (EMG), isometric force dynamometry, and modified Bromage scale. To test abdominal muscle strength, an EMG lead was placed over the body of the rectus abdominus muscle to the left of the umbilicus. A restraining strap was placed across the body at the level of the xiphoid, and an isometric maximal contraction of abdominal muscle flexion against the strap was conducted. Using a commercially available surface EMG (MyoTrac2; Thought Technology Ltd., Montreal, PQ), an averaged, rectified measurement was taken during the middle 2 s of a 6-s maximal effort. Muscle strength of the right lower extremity was measured using a commercially available isometric force dynamometer (Micro FET; Hoggan Health Industries, Draper, UT), during a 5-s maximal force contraction of the right quadriceps muscle (straight leg lift against resistance) and right gastrocnemius (plantar flexion against resistance). Measurements for both tests were performed in triplicate and averaged at baseline and at 10-min intervals after injection until >90% of baseline strength returned. Modified Bromage scores (0 = no block, 1 = able to bend the knee, 2 = able to dorsiflex the foot, and 3 = complete motor block) were recorded every 10 min after injection until the resolution of the motor block or until 40 min if no motor block was achieved.
Each subject underwent a simulated clinical discharge pathway. On recovery of the S2 dermatome to pinprick, the subjects attempted ambulation without assistance. If ambulation was successful, they then attempted to void. If either ambulation or voiding was unsuccessful, then the attempts were repeated at 10-min intervals until these end-points were achieved. Volunteers were questioned daily for 72 h regarding the presence of headache, backache, or other symptoms.
Bilateral measurements were averaged for each subject. Paired Student’s t-tests were used to determine differences between anesthetics in each subject. Repeated-measures analysis of variance was used for continuous variables, and χ2 analysis was used for incidence data. Unless otherwise specified, data are mean ± sd, with significance defined as P < 0.05.
Successful spinal anesthesia was obtained in all subjects (3 female, 5 male; age, 35 ± 6 yr; weight, 79 ± 19 kg; height, 173 ± 7 cm). Subjects received 400 ± 222 mL of IV lactated Ringer’s solution. 2-chloroprocaine was similar to lidocaine in pertinent measures of surgical efficacy including peak block height, tourniquet tolerance, and tolerance of TES equivalent to surgical incision (Table 1, Fig. 1). 2-chloroprocaine was associated with faster resolution of sensory anesthesia and earlier attainment of commonly used discharge criteria, including time to complete regression and voiding (Table 1, Fig. 2). Although there was a tendency for 2-chloroprocaine to produce a shorter duration of motor blockade (Fig. 3), this did not reach statistical significance (Table 1). Sacral sparing was noted in two subjects, one after a lidocaine spinal anesthetic and one after a 2-chloroprocaine spinal anesthetic. Three subjects had tourniquet tolerance of <30 min with lidocaine spinals; all subjects had tourniquet tolerance of >30 min with 2-chloroprocaine spinal anesthesia.
Hemodynamic changes were mild, and did not vary significantly between groups (Fig. 4). No vasoactive drugs were required.
No subjects complained of headache after either anesthetic. Of note were complaints of low back pain with radiation to the hips, buttocks, or lower extremities consistent with TNS in 7 of 8 subjects after receiving lidocaine spinal anesthesia. These symptoms started 0–36 h after the resolution of spinal anesthesia, lasted for 24–72 h, and were rated by subjects as having a mean visual analog score of 4.7, with a range of 2–8. No subject reported symptoms of TNS after receiving 2-chloroprocaine spinal anesthesia (χ2, P = 0.004) (Table 2). One subject complained of ab- dominal pain and constipation for 2 days after the 2-chloroprocaine spinal; otherwise, there were no complaints of side effects after 2-chloroprocaine spinal anesthesia.
This study demonstrates that spinal anesthesia with 40 mg of preservative-free 2-chloroprocaine produces an equivalent quality of surgical anesthesia compared to 40 mg lidocaine. Onset and peak block height were similar in both groups. Tourniquet tolerance was similar in both groups, though we must note that tourniquet times were unacceptably short during lidocaine spinals for 3 subjects, suggesting that 40 mg plain lidocaine may not be sufficient for procedures where prolonged tourniquet use is anticipated. Sedation with benzodiazepines or propofol, as is common with many regional anesthetics, may extend the duration of tourniquet tolerance during surgical procedures. Previous studies have shown TES to 60 mA to be an equivalent stimulus to surgical incision during general anesthesia, and tolerance of TES stimulation likely represents a reasonable facsimile to surgical conditions under regional anesthesia (11,12). We found the duration of both sensory and motor block is shorter with 2-chloroprocaine, resulting in an earlier time to void and ambulate.
Some clinicians have advocated use of small-dose bupivacaine in lieu of lidocaine, as the incidence of TNS is significantly less (13). Small-dose spinal bupivacaine does not reliably provide motor block (14), and larger doses may delay discharge because of prolonged sensory blockade and failure to void, making it less attractive for outpatient procedures. Unlike small-dose bupivacaine, 2-chloroprocaine spinal anesthesia reliably produces profound lower extremity motor block, which is desirable for many surgical procedures. 2-chloroprocaine also produces a more predictable duration of sensory anesthesia, with standard deviations of <20 min for all measurements. In contrast, small-dose spinal bupivacaine has been shown to be quite variable in duration, with a 3.75-mg dose of bupivacaine resulting in 73 ± 43 min of TES tolerance at S2 (15).
Procaine, another short-acting ester anesthetic, has an infrequent incidence of TNS (16) but has been associated with a 14%–17% incidence of clinical block failure (16,17) and prolonged discharge from outpatient procedures because of nausea, vomiting, and other side effects (16,18). Ester anesthetics such as procaine and 2-chloroprocaine can provoke allergic reactions in patients sensitive to p-aminobenzoic acid. Skin sensitivity is relatively common, but serious allergic reactions are rare. We are unaware of any clinical studies directly comparing spinal 2-chloroprocaine with either bupivacaine or procaine.
The incidence of TNS with spinal lidocaine in our study was surprisingly frequent, occurring in 7 of 8 subjects. Surgical patients taking NSAIDS or narcotics after surgery may be less likely to have symptoms of TNS. Concurrent use of sedatives, hypnotics, or analgesics commonly given to surgical patients during block placement or the surgical procedure may also reduce the incidence of TNS. We speculate that the study design itself, with frequent use of low back (sit-ups) and lower extremitiy (leg lifts) muscles may also have contributed to an increased incidence of these symptoms. However, the randomized, double-blinded crossover study design included these same maneuvers in each subject for each spinal anesthetic. There were no complaints of TNS after 2-chloroprocaine spinal anesthesia. Therefore, despite a small number of subjects and an unusually frequent incidence of TNS with lidocaine, the intraindividual difference clearly suggests that subarachnoid block with 2-chloroprocaine is less likely to be associated with TNS.
Reliable achievement of discharge criteria is of great interest in an outpatient setting. We evaluated several commonly used discharge criteria in our unsedated volunteers, including resolution of sensory anesthesia, independent ambulation, and voiding. 2-chloroprocaine spinal anesthesia produced earlier attainment of all discharge criteria. This may not predict actual discharge times in surgical patients, who frequently receive sedation and narcotics during the perioperative period. Other side effects such as nausea, vomiting, and urinary retention can also delay discharge in surgical patients but were not seen in this small sample.
Reports of persistent neurotoxicity after intrathecal injection of large volumes of preservative-containing 2-chloroprocaine intended for the epidural space have been well reviewed in the anesthesia literature (2). In short, it has been shown that sodium bisulfate and metabisulfite, used as preservatives, are neurotoxic when combined with acidic formulations of local anesthetics. Although the literature is somewhat divided, most clinicians have concluded that the injuries reported from injection of large doses of Nescaine-CE in the intrathecal space were most likely caused by neurotoxicity from this preservative. No convincing evidence exists to suggest that preservative free 2-chloroprocaine is neurotoxic in doses appropriate for spinal anesthesia.
A second preservative, EDTA, has been implicated as a possible cause of back pain after epidural injection of 2-chloroprocaine; this formulation is no longer commercially available. The pain syndrome experienced after epidural anesthesia with 2-chloroprocaine is distinctly different from TNS. It consists of localized low back pain without radiation or radicular symptoms, with onset immediately after the resolution of anesthesia (19). It is thought to be dose-related and occurs most frequently with doses of 400 mg or more of 2-chloroprocaine.
Intrathecal injection of preservative-free 2- chloroprocaine compares favorably with lidocaine for ambulatory anesthesia, providing equivalent surgical anesthesia with earlier block resolution, more rapid attainment of commonly used discharge criteria, and no evidence of TNS. Larger clinical trials are underway to further address questions of safety and efficacy of 2-chloroprocaine for ambulatory spinal anesthesia.
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