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REGIONAL ANESTHESIA

Spinal 2-Chloroprocaine: A Comparison with Small-Dose Bupivacaine in Volunteers

Department of Anesthesiology, Virginia Mason Clinic, Seattle, Washington

	Abstract

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Ambulatory surgery continues to increase nationwide. Because spinal lidocaine is associated with transient neurologic symptoms, many clinicians have switched to small-dose bupivacaine for outpatient spinal anesthesia. However, bupivacaine often produces inadequate surgical anesthesia and has an unpredictable duration. Preservative-free 2-chloroprocaine (2-CP) has reemerged as an alternative for outpatient spinal anesthesia. We designed this double-blind, randomized, crossover, volunteer study to compare 40 mg of 2-CP with small-dose (7.5 mg) bupivacaine with measures of pinprick anesthesia, motor strength, tolerance to tourniquet and electrical stimulation, and simulated discharge criteria. Peak block height (2-CP average T7 [range T3–10]; bupivacaine average T9 [range T4–L1]), regression to L1 (2-CP 64 ± 10 versus bupivacaine 87 ± 41 min), and tourniquet tolerance (2-CP 52 ± 11 versus bupivacaine 60 ± 27 min) did not differ between drugs (P = 0.15, 0.12, and 0.40, respectively). However, time to simulated discharge (including time to complete block regression, ambulation, and spontaneous voiding) was significantly longer with bupivacaine (2-CP 113 ± 14, bupivacaine 191 ± 30 min, P = 0.0009). No subjects reported transient neurologic symptoms or other side effects. We conclude that spinal 2-CP provides adequate duration and density of block for ambulatory surgical procedures, and has significantly faster resolution of block and return to ambulation compared with 7.5 mg of bupivacaine.

	Introduction

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Ambulatory surgical procedures are steadily increasing nationwide, and anesthesiologists are driven to provide fast turnover, predictable anesthesia, and time-efficient discharge of patients (1). Many clinicians are selecting general anesthesia because of its relative predictability and to avoid undesirable side effects associated with spinal anesthesia (2). For example, lidocaine is frequently associated with transient neurologic symptoms (TNS), procaine is often unpredictable in duration and is associated with a frequent incidence of nausea, and bupivacaine causes frequent urinary retention, prolonged discharge time, and unpredictable levels of anesthesia dependent on dose (3–6). Recently, 2-chloroprocaine (2-CP) has been evaluated for use in the subarachnoid space and seems to be a predictable drug, ideal for clinicians working in fast-paced ambulatory surgical settings.

Preservative-free 2-CP was first introduced in 1952 and was used successfully for spinal anesthesia (7). Preservatives and antioxidants were subsequently added, and the drug was primarily used as an epidural anesthetic in the obstetric population. After several reports of severe neurotoxicity after inadvertent subarachnoid injection of large volumes of 2-CP, the drug was no longer used for spinal anesthesia (8–10). Subsequently, the antioxidant sodium bisulfite, in an acidic environment, was often accepted to be the culprit in these cases. Although all preservatives and antioxidants have been removed from 2 of the 3 currently available preparations of 2-CP, until recently, the anesthesia community was reluctant to reintroduce 2-CP as a spinal anesthetic.

The use of 2-CP for spinal anesthesia has been studied as a short-acting drug with a favorable profile for outpatient surgery. Four randomized controlled preclinical trials have investigated spinal 2-CP in healthy volunteers (11–14) finding a predictable onset, block height, and time to complete regression. In addition, a recent chart review of the first 122 patients at our institution, and a description of the first 500 patients from another institution, have demonstrated 2-CP to be free of apparent neurotoxicity or TNS (15,16).

Small-dose bupivacaine (5–7.5 mg) has also been used by some practitioners for spinal anesthesia in attempts to avoid side effects associated with lidocaine and procaine.

Disadvantages with small-dose bupivacaine also exist, including inadequate block height for the surgical procedure, urinary retention, or an excessively long time-course to block resolution which delays discharge (17). Ben-David et al. (18) demonstrated that 7.5 mg of 0.5% bupivacaine with dextrose provided an acceptable spinal anesthetic for ambulatory surgery when compared with both smaller and larger doses of plain bupivacaine.

Although the clinical characteristics of spinal 2-CP have been shown to be similar to lidocaine (11), direct comparison to small-dose spinal bupivacaine has not been performed. This randomized, double-blind study was designed to compare 2-CP (40 mg) to small-dose bupivacaine (7.5 mg) in 8 healthy volunteers using a crossover design.

	Methods

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After written informed consent and IRB approval were obtained, eight healthy volunteers were enrolled in the crossover study. All volunteers were informed that the preservative-free formulation of 2-CP for spinal anesthesia was an off-label use of the drug. A random number generator was used to determine the order of local anesthetic to be used and all solutions were prepared by Virginia Mason anesthesiologists who did not reveal the identity of the solution to the investigators. The two spinal anesthetics were separated by at least 96 h. The two local anesthetic solutions were diluted to a total volume of 2.25 mL, calculated to be of comparable baricity (slightly hyperbaric, density approximately 1.00100 g/mL) (19,20): 1) preservative-free 2-CP (40 mg: 2 mL 2% with 0.25 mL preservative-free normal saline), and 2) preservative-free bupivacaine (7.5 mg: 1.5 mL 0.5%, 0.5 mL sterile saline, and 0.25 mL dextrose). Two preservative- and bisulfite-free formulations of 2-CP are now available commercially: Nesacaine-MPF (AstraZeneca Pharmaceuticals, Worchester, MA), and generic CP (Bedford Laboratories, Bedford, OH). The AstraZeneca formulation (Nesacaine-MPF) (pH 2.7–4.0) was used in this study. No sedatives were administered and all subjects had fasted for 8 h before enrollment. A 20-gauge peripheral IV catheter was placed and a bolus of lactated Ringer’s solution was administered (approximately 5 mL/kg) before subarachnoid injection of local anesthetic. All subjects were placed in the left lateral decubitus position and a prep solution was applied to the skin of the lumbar region. Using a 30-gauge needle, a skin wheel was raised with 1% lidocaine over the L2–3 interspace. The subarachnoid space was entered via the midline approach using a 20-gauge introducer and a 24-gauge Sprotte needle. The rate of injection of the study medication was approximately 0.25 mL/s with the spinal orifice of the needle facing in the cephalad direction. After administration of the drug, approximately 0.2 mL of cerebrospinal fluid was aspirated to confirm position in the subarachnoid space. Subjects were immediately placed in the supine position where they remained for the duration of the study.

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 every 10 min 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: bilaterally at the lateral ankle (S1), medial knee (L3), and at the midline pubis (T12) and midline umbilicus (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 milliampere (mA) followed by increasing increments of 10 mA to a maximum of 60 mA. Previous studies have shown TES of 60 mA is equivalent to the intensity of surgical incision supporting a maximum of 60 mA of stimulation for this study (21). TES was performed in a cephalad-to-caudad direction beginning at 4 min after injection and proceeding at 10-min intervals thereafter until the subject was no longer able to tolerate the 60-mA stimulation on 2 successive tests. If the subject was never able to tolerate 60 mA, the testing was terminated at 34 min.

Thigh tourniquet tolerance time was assessed for all subjects using a 34-in. pneumatic cuff inflated to 300 mm Hg after exsanguination of the left leg by gravity. The cuff was routinely inflated 30 min after injection of local anesthetic. Cuff pressure in this study was similar to that used in orthopedic procedures performed at our institution. When the pain score reached 5 of 10 on the visual analog scale scoring system for subjects, the tourniquet was deflated and total tourniquet time was recorded.

Motor block of the lower extremity was assessed using a Bromage scale of 0–3 (0 = full straight leg raise, 1 = able to bend knee, 2 = unable to bend knee, able to dorsiflex ankle, 3 = no motor movement). Measurements were taken every 10 min after injection of local anesthetic until bilateral scores of "0" were regained. In addition, isometric force dynamometry (Micro FET; Hoggan Health Industries, Draper, UT) was used to assess motor blockade of the right lower extremity. Data were collected for both quadriceps strength (dynamometry at inferior thigh with straight leg raise) and gastrocnemius strength (dynamometry with plantar flexion of the foot). All measurements were collected in triplicate and averaged at 10-min intervals after injection until >90% of baseline strength had returned.

All subjects underwent a simulated clinical discharge pathway with block resolution. Upon recovery of the S2 dermatome to pinprick bilaterally, a bladder ultrasound was performed to assess prevoid bladder volume using a commercially available bladder ultrasound (Bladderscan BV12500; Diagnostic Ultrasound Corp., Kirkland, WA). If subjects were then able to ambulate without assistance, they were asked to void spontaneously. If either ambulation or voiding were unsuccessful, attempts were repeated at 15-min intervals until end-points were achieved. After successful ambulation and voiding were achieved (defined as "discharge time"), a postvoid residual bladder volume was assessed by repeat ultrasound. Upon completion of the study, volunteers were questioned daily for the following 72 h for symptoms including backache, headache, inability to void, or other residual symptoms, and were recontacted after 6 mo for long-term follow-up.

Using a difference of 15 min in time to complete sensory resolution, a standard deviation of 10 min, and an = 0.05 with ß = 0.80, 8 subjects were required. An integer was assigned to each dermatomal level (i.e., T10 = 10, T9 = 11, T8 = 12, T12 = 8, etc.) for statistical analysis of dermatomal height. All dermatomal levels blocked to pinprick were averaged for each local anesthetic to determine the estimated time course of recovery to sensory anesthesia. The Mann-Whitney U-test was used to compare peak block height between the two drugs. Comparisons of dermatome regression over time, isometric force dynamometry, and hemodynamic data were made using repeated-measures analysis of variance with Bonferroni-Dunn test for post hoc analysis. Differences between anesthetics for all other measurements were analyzed using paired Student’s t-test. Data are mean ± sd with significance defined as P < 0.05.

	Results

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All 8 subjects developed sensory anesthesia after spinal injection on 2 separate occasions with both 2-CP and bupivacaine (4 women, 4 men; age 38 ± 7 yr; weight 154 ± 36 kg; height 170 ± 10 cm). Subjects received 681 ± 96 mL of lactated Ringer’s solution.

Spinal 2-CP 40 mg and bupivacaine 7.5 mg produced similar peak block height, time to peak block, and regression to the L1 dermatome (Fig. 1), (Table 1). There was no significant difference in tourniquet tolerance time between the two drugs, although 1 subject in each group tolerated the tourniquet for <30 min (Fig. 2). There was also no significant difference in TES tolerance at the T10, T12, or L5–S1 dermatomes between the 2 groups. However, 3 of the subjects in the bupivacaine group never tolerated >40 mA at the T12 or T10 dermatome whereas all subjects in the 2-CP group tolerated TES of 60 mA at the T12 dermatome for at least 30 min. There was a significant difference between the 2 groups at the L2–3 dermatome as subjects with 2-CP anesthesia tolerated maximal TES at this dermatome for a shorter period of time than the bupivacaine group (P = 0.03 and 0.01, (Fig. 2).

View larger version (30K): [in this window] [in a new window]   Figure 1. Sensory peak block height and dermatomal regression to pinprick comparing 2-chloroprocaine and bupivacaine over time (analysis of variance, P < 0.01).

View larger version (33K): [in this window] [in a new window]   Figure 2. Thigh tourniquet tolerance time (placed 30 min after injection) and duration of tolerance to simulated surgical stimulus (transcutaneous electrical stimulation of 60 mA).

There was no significant difference in motor block between the two drugs with regard to Bromage scale of lower extremity strength. Of note, 3 subjects with bupivacaine spinal anesthesia never reached a Bromage scale >1 compared with 2-CP where all reached a bilateral Bromage scale of 3 for at least 25 min (Table 1). Lower extremity strength was also assessed by dynamometry measurements. For both quadriceps and gastrocnemius muscle strength, the use of spinal 2-CP when compared with bupivacaine resulted in significantly faster return of motor strength (Fig. 3).

View larger version (36K): [in this window] [in a new window]   Figure 3. A, Resolution of motor block for gastrocnemius muscle measured by isometric force dynamometry (repeated-measures analysis of variance, P < 0.01). B, Resolution of motor block for quadriceps muscle measured by isometric force dynamometry (repeated-measures analysis of variance, P < 0.01).

2-CP also resulted in a significantly faster time to complete resolution of block, time to ambulation, and time to voiding compared with bupivacaine (Fig. 1), (Table 1).

There was no significant variation in hemodynamic measurements between groups (repeated-measures analysis of variance, P > 0.05). One subject with bupivacaine spinal anesthesia was treated with ephedrine 10 mg for slight nausea and heart rate = 42. No subjects reported any adverse symptoms, including TNS or other neurologic symptoms, immediately after either spinal anesthetic, through the 72-h observation period, or after 6 mo follow-up.

	Discussion

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Small-dose bupivacaine has been used for spinal anesthesia for procedures of short duration in attempts to avoid local anesthetics such as lidocaine and procaine, known to cause adverse side effects such as TNS and nausea, respectively. This study was designed to directly compare the minimally reliable dose of spinal bupivacaine (7.5 mg) to 40 mg of spinal 2-CP in healthy volunteers in a simulated ambulatory surgical setting.

There was no significant difference in peak block height or time to peak block height between the two drugs, or for time to regression to the L1 dermatome. Although subjects in the bupivacaine group were able to tolerate the thigh tourniquet for a significantly longer time as a group, the variation was broad. All subjects in the 2-CP group tolerated the tourniquet for at least 25 minutes, which is adequate for most knee and ankle arthroscopies at our institution. Clinically, the use of sedation may further prolong the tolerance to thigh tourniquet during actual surgical procedures.

Although no statistical difference between the two groups for motor strength as assessed by Bromage scores was found, the variability within the bupivacaine group was striking (Table 1). One subject was able to perform a full straight leg lift throughout his anesthetic and 2 in this group never reached a score >1 (still able to actively bend the knee). In the remaining 5 subjects in the bupivacaine group, the time lapse going from no motor movement (score of 3) back to a full straight leg raise (score of 0) was widely variable (20–60 minutes). In contrast, this time averaged 15 minutes for spinal 2-CP, with many subjects going from Bromage 3 to 0 in a single 10-minute assessment period. Incomplete lower extremity muscle relaxation is often a detriment in lower extremity orthopedic surgery (i.e., knee arthroscopy) because surgeons find these operating conditions to be unacceptably challenging. Therefore, small-dose bupivacaine may be less desirable than 2-CP when full relaxation is desired for a brief period of time.

The reintroduction of 2-CP as a spinal anesthetic has progressed with caution given its history. As previously stated, when the formulation containing preservatives in a low pH was inadvertently injected into the subarachnoid space in large doses, significant morbidity resulted for a least 8 patients (8–10). Subsequent laboratory studies have been somewhat contradictory as to the cause of neurotoxicity. Early laboratory studies demonstrated the antioxidant bisulfite at a low pH as a cause, whereas a more recent study has questioned this mechanism (22–24).

Within the last year, 4 randomized-controlled trials in healthy volunteers illustrated that preservative-free formulations of 2-CP provide predictable and dense spinal anesthesia for short, ambulatory procedures (11–14). The clinical use of a preservative-free formulation of 2-CP in 122 patients over a 10-month period at our institution has been recently reported, with all patients having excellent anesthesia for procedures of <60 minutes and no reports of TNS or neurotoxicity (15).

One criticism of the current study could be the variables of the simulated discharge. Although it is the current standard of care to wait until sensory anesthesia has completely resolved before discharging a patient after spinal anesthesia, the results may have been different if sensory block regression was not used as a prerequisite for ambulation and spontaneous voiding. Because bupivacaine has an especially variable course in terms of recovery of motor block, the results may have been biased toward the CP group.

An additional criticism of the current study design could be that the dose of bupivacaine chosen (7.5 mg) was too large. Ideally, thorough dose-response curves (3+ doses) would be generated for each drug, which would preclude the use of our crossover design and require a much larger number of subjects. We instead chose to study the smallest dose of each drug believed to be clinically reliable without the addition of additives. Ben-David et al. (18) have shown that 7.5 mg of plain bupivacaine provides adequate spinal anesthesia for lower extremity surgery. Plain bupivacaine in doses <7.5 mg has been shown to be unreliable for surgical procedures of the lower extremity or abdomen. Failure rates for smaller doses (5–6 mg) of plain spinal bupivacaine range from 24% to 80%, depending on the surgical procedure (6,18,25,26). In some studies, the combination of small-dose bupivacaine with fentanyl provides more predictable surgical anesthesia compared with small-dose bupivacaine alone (6,27). Bupivacaine in a dose of 4 mg with fentanyl has been used successfully for surgical anesthesia (27). The authors considered this when designing the study, although based on the previous randomized-controlled trial of 40 mg of 2-CP with and without fentanyl, the incidence of pruritus in the fentanyl group was unacceptably frequent (7 of 8 volunteers) (13). We chose instead to compare additive-free formulations of both anesthetics in an attempt to avoid comparing one drug with and one drug without an additive.

In conclusion, this study has shown that 2-CP is a better alternative than 7.5 mg of plain bupivacaine for outpatient spinal anesthesia. Although there were not significant differences in peak block height, 2-CP spinal anesthesia consistently resulted in faster resolution of block, time to ambulation, and voiding under our simulated conditions in volunteers. These data await validation in a surgical patient population.

	Footnotes

 
This work was supported by the Department of Anesthesiology, Virginia Mason Medical Center.

Portions of this work were presented at the American Society of Regional Anesthesia 29th Spring Meeting, Orlando, FL, March 2004.

Although 2-chloroprocaine is approved by the FDA, it is not specifically indicated for spinal anesthesia. Its use for spinal anesthesia is thus considered "off-label." Manufacturers of 2-chloroprocaine distinctly label product "Not for Spinal Anesthesia."

Accepted for publication August 10, 2004.

Address correspondence to Dr. Dan J. Kopacz, Department of Anesthesiology, Virginia Mason Clinic, 1100 Ninth Ave., B2-AN, Seattle, WA 98111. Address e-mail to dan.kopacz{at}vmmc.org.

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