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Anesth Analg 2005;100:573-579
© 2005 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000143380.36298.4A

REGIONAL ANESTHESIA

Spinal 2-Chloroprocaine: A Comparison with Procaine in Volunteers

Aaron F. Gonter, MD, and Dan J. Kopacz, MD

Department of Anesthesiology, Virginia Mason Medical Center, Seattle, Washington


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Recent studies using preservative-free 2-chloroprocaine (2-CP) for spinal anesthesia have shown it to be a reliable short-acting drug that provides similar anesthesia to lidocaine. In this randomized, double-blind, crossover study, we compared the characteristics of spinal 2-CP (30 mg) with those of procaine (80 mg) in eight volunteers to determine whether either drug produces spinal anesthetic characteristics ideal for outpatient surgery. By using sensation to pinprick, transcutaneous electrical stimulation, tolerance to thigh tourniquet, and motor blockade as surrogates for surgical efficacy, 2-CP compared similarly to procaine. Peak block height (T9 [range, T6 to T12] versus T6 [T4 to T8]; P = 0.0796), time to two-segment regression (51 ± 17 min versus 53 ± 10 min; P = 0.7434), tourniquet time tolerance (37 ± 16 versus 49 min ± 17 min; P = 0.1755), and time to return of motor strength (Bromage scale: 54 ± 23 min versus 55 ± 44 min, P = 0.9366; return of 90% quadriceps strength: 78 ± 9 min versus 98 ± 30 min; P = 0.0721) were all similar. Procaine did produce overall longer sensory blockade (P = 0.0011) and motor blockade at the gastrocnemius (P = 0.0004) and quadriceps (P = 0.0146) muscles. Times until the resolution of sensory blockade (103 ± 12 min versus 151 ± 26 min; P = 0.0003), ambulation (103 ± 12 min versus 151 ± 26 min; P = 0.0003), and micturition (103 ± 12 min versus 156 ± 23 min; P < 0.0001) were all prolonged after procaine. In conclusion, at the doses tested, spinal 2-CP (30 mg) may be a better choice for short outpatient procedures because it provides anesthesia with similar efficacy as procaine (80 mg) but with more rapid fulfillment of discharge criteria.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
As the popularity of regional anesthesia and outpatient surgery has grown, so has the search for a short-acting spinal anesthetic with a predictable duration, quick resolution, and lack of side effects. Efforts to find the ideal intrathecal doses of lidocaine, bupivacaine, and procaine for outpatient surgery have only uncovered these drugs' shortcomings. Lidocaine is associated with a 27%–30% risk of transient neurologic symptoms (TNS) (1,2). Bupivacaine, even in doses as small as 5 mg with fentanyl, can cause a prolonged time until voiding and discharge (3). Procaine, considered the shortest-acting drug, has the most frequent incidence of nausea and inadequate anesthesia (1,2,4–6).

Recent studies have shown that spinal 2-chloroprocaine (2-CP) has characteristics ideal for short outpatient procedures such as knee arthroscopy (7–9). 2-CP was first described as a spinal anesthetic in 1952 and was considered a reliable and safe anesthetic because of its potency, rapid onset, and rapid hydrolysis by plasma esterase (10). Over the next 30 yr, it became popular as an epidural anesthetic, especially in obstetrics. In the 1980s, there were reports of neurologic deficits in eight patients after epidural anesthesia with 2-CP (11–13). Several investigations conducted at that time concluded that these injuries were caused by the combination of low pH and the antioxidant sodium bisulfite in the 2-CP preparation, although a recent animal study debated these results (14–16). 2-CP is currently available in a preparation that is both preservative and antioxidant free. This preparation is similar to the one used in 1952, and its availability has renewed interest in 2-CP as a spinal anesthetic.

Procaine, the predecessor to 2-CP, has been used extensively for spinal anesthesia. It is considered an alternative to lidocaine because of its short duration and less frequent incidence of TNS (0%–3%) (1,2,17). However, prospective randomized trials of procaine in the 1990s showed that it is an unreliable drug with a frequent incidence of side effects (1,2,4,5,17). The incidence of inadequate anesthesia was 14%–17%, and the incidence of nausea was 10%–17%, compared with lidocaine, which has a 3% incidence for both (1,2). Even though 2-CP is a derivative of procaine, their use in the subarachnoid space has never been compared prospectively. This randomized, double-blind, crossover study was designed to compare the characteristics of spinal anesthesia after 30 mg of 2-CP and 80 mg of procaine in an established volunteer model.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Eight healthy volunteers were enrolled after IRB approval and written informed consent. All subjects were informed that 2-CP is labeled by manufacturers as "not for spinal anesthesia." Each subject received 2 spinal anesthetics, 1 with 30 mg of 2-CP and another with 80 mg of procaine, separated by at least 48 h. The 2-CP was prepared by diluting 1 mL of 3% 2-CP with 1 mL of saline to yield of a 1.5% solution. 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) was used in this study. The procaine was prepared by mixing 0.8 mL of 10% procaine with 1.2 mL of saline to yield a 4% solution. Although the densities of these 2-CP and procaine mixtures were not directly measured, extrapolating from previous measurements, we believe they are both slightly hyperbaric and of comparable density. A random-number generator was used to determine the order of drug administration for each subject. All volunteers received nothing by mouth for more than 6 h for solids and 2 h for liquids. Each voided before the administration of the spinal anesthetic. A 20-gauge peripheral IV cannula was placed, and lactated Ringer's solution was administered at 8 mL/kg for 1 h, followed by 2 mL · kg–1 · h–1. No sedatives were used, and vasopressors were available to treat symptomatic decreases in heart rate or arterial blood pressure, if needed.

Each spinal anesthetic was performed with the subject in the left lateral position by using an aseptic technique. A 24-gauge Sprotte needle was inserted at the L2-3 interspace with the orifice pointing cephalad. Cerebrospinal fluid 0.2 mL was aspirated to confirm needle placement, followed by injection of 2 mL of the study solution over approximately 10 s. After injection, another 0.2 mL of cerebrospinal fluid was aspirated to again confirm placement. The subjects were immediately turned supine for the rest of the study.

Noninvasive arterial blood pressure, pulse oximetry, and electrocardiogram were monitored. Arterial blood pressure and heart rate were recorded at baseline and at 5-min intervals during the study. Sensory anesthesia was assessed with pinprick by using the forearm as a control. Dermatome levels to pinprick were recorded every 5 min for the first 60 min and every 10 min thereafter until regression to S2.

To simulate surgical stimulation, transcutaneous electrical stimulation (TES) was tested midline at the umbilicus (T10) and pubis (T12), as well as bilaterally at the medial knee (L3) and lateral ankle (S1). This was performed with a peripheral nerve stimulator (Model NSS25; Fisher and Paykel, Auckland, New Zealand) with a 50-Hz tetanus for 5 s. Each site was initially tested with 10 mA. The current was then increased in increments of 10 mA until either the subject reported discomfort or the maximum of 60 mA was attained. In previous studies, this maximum limit has been shown to be of comparable intensity to skin incision (18). TES was performed 4 min after the administration of the anesthetic and every 10 min thereafter until two consecutive measurements of <60 mA were recorded. If this maximum current was not tolerated at any site, then that site was stimulated with the highest tolerable current at the same interval for a minimum of 34 min.

Tolerance to a left thigh tourniquet was assessed 30 min after placement of the spinal anesthetic. The leg was passively exsanguinated by gravity before inflation of the tourniquet to 300 mm Hg. It was deflated when requested by the subject, and the duration from inflation to deflation was recorded.

Motor strength was measured by using an isometric force dynamometer (Micro FET; Hoggan Health Industries, Draper, UT) at the right knee and ankle. Subjects were instructed to perform 3 5-s maximal force straight-leg lifts (quadriceps), followed by 3 5-s maximal force plantar flexions of the foot (gastrocnemius). The average of the 3 measurements was recorded at baseline and at 10-min intervals until more than 90% of baseline strength returned. Lower-extremity movement was also assessed every 10 min by using the modified Bromage scale (0 = no block, 1 = able to bend knee, 2 = able to dorsiflex the foot, and 3 = complete motor block).

To simulate discharge criteria, each subject received a bladder ultrasound when recovery of sensation at the S2 level occurred. The prevoid bladder volume was recorded, and subjects were allowed to ambulate. If they successfully ambulated without assistance, then they were instructed to void. After they voided, a second bladder ultrasound was performed to determine the postvoid residual bladder volume.

By using an estimated difference of 15 min for the time to complete sensory resolution between drugs, an sd of 10 min, and an {alpha} = 0.05 with ß = 0.80, 8 subjects were required. All data are reported as mean ± sd unless otherwise noted, and a P value <0.05 was considered significant. All bilateral measurements were averaged. Paired Student's t-tests were used to determine differences between anesthetics in each subject, except in the case of peak block height, which was analyzed with the Mann-Whitney U-test. Continuous variables were compared by using repeated-measures analysis of variance with Bonferroni/Dunn tests for post hoc analysis.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Four men and four women were enrolled in the study. Age (42 ± 11 yr), weight (73 ± 20 kg), height (66 ± 6 in.), and volume of infused lactated Ringer's solution (735 ± 177 mL) were recorded for each subject. Sensory anesthesia to pinprick was achieved in all volunteers. There were no significant differences between 2-CP and procaine in tourniquet time, peak block height, time to peak, time to two-segment regression, and tolerance to TES at T10 (Table 1, Fig. 1). However, other measures of surgical efficacy—such as regression of sensory blockade to L1 and tolerance to TES at T12, L3, and S1—were significantly longer in the procaine group (Table 1, Fig. 1). Sensory block to pinprick did not become significantly different until 45 min (Fig. 2). Motor blockade was similar between groups when assessed by the Bromage scale (Table 1). When assessed by dynamometry, motor blockade was longer in the procaine group (Fig. 3). However, the time to recover 90% of baseline quadriceps strength was not significantly different. In regard to simulated discharge criteria, the times until complete regression of sensory block, ambulation, and micturition were all significantly longer in the procaine group (Table 1, Fig. 1). There were no significant differences between groups in post-void residual volume (Table 1).


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  		Table 1. Clinical Data

 


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  		Figure 1. Duration of tolerance to simulated surgical stimulus (transcutaneous electrical stimulation [TES] of 60 mA) by dermatomes, tolerance to thigh tourniquet placed 30 min after injection, and time until completion of simulated discharge criteria, including time to ambulation and voiding. All analyses are paired Student's t-tests averaged for bilateral measurements. *P < 0.05.

 


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  		Figure 2. Resolution of sensory blockade as measured by pinprick anesthesia: 2-chloroprocaine versus procaine (P = 0.0011).

 


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  		Figure 3. Resolution of motor blockade as measured by isometric force dynamometry at (A) the quadriceps (P = 0.0146) and at (B) the gastrocnemius (P = 0.0004) muscles.

 

Two of eight subjects in the 2-CP group attained a peak block height to only the L1 dermatome. One of these subjects had sacral sparing and the shortest tourniquet time in the study (6 min). The other subject tolerated the tourniquet for 37 min. All other subjects in the 2-CP group tolerated the tourniquet for >30 min. The shortest tourniquet time in the procaine group was 30 min.

The only side effects occurred in the procaine group: one subject reported subtle pruritus as the spinal anesthesia regressed, and another reported feelings of dysphoria during the spinal. There were no reports of radiating or nonradiating back pain. No subject required vasopressors for hypotension.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In this study, we demonstrated that spinal anesthesia after 30 mg of 2-CP has characteristics better suited than 80 mg of procaine for short outpatient procedures. Because procaine produced significantly longer tolerance to TES and higher sensory levels after 45 minutes, satisfaction of simulated discharge criteria took an average of 50 minutes longer for subjects receiving procaine compared with 2-CP.

When choosing a drug for spinal anesthesia, the clinician must consider patient and surgical factors, as well as the characteristics of the drug itself. In the outpatient setting, one of the most important considerations is the ability of the patient to meet discharge criteria as soon as possible in the recovery area. However, this goal should not come at the expense of providing reliable and adequate spinal anesthesia. Recent studies with 40 mg of 2-CP have shown that it can produce surgical conditions with similar efficacy as lidocaine but with earlier resolution of blockade and no reports of TNS (7). The addition of fentanyl prolongs sensory blockade and only minimally extends the time to achieve simulated discharge criteria (9). We chose to study the effects of a smaller dose of 2-CP (30 mg) to determine whether this smaller dose also produces adequate anesthesia.

Because both procaine and 2-CP are classified as short-acting ester local anesthetics, we designed this study to directly compare their clinical characteristics. We demonstrated that 30 mg of 2-CP provides tourniquet tolerance similar to that with 80 mg of procaine: all but one subject in the 2-CP group tolerated the tourniquet for >30 minutes. Sensory blockade was not significantly different with respect to peak block height, time to peak, and time to two-segment regression. Sensory levels did not become significantly different until 45 minutes, when the average sensory levels were T11 and T8 for the 2-CP and procaine groups, respectively. Likewise, when motor blockade was measured by dynamometry, there were no significant differences until 70 minutes at the gastrocnemius and 80 minutes at the quadriceps. The procaine group had the longer duration. The tolerance to TES, a surrogate for surgical stimulation, was significantly longer in the procaine group. In fact, tolerance to TES at S1 lasted 109 ± 28 minutes, which was longer than the average time to meet simulated discharge criteria in the 2-CP group (103 ± 12 minutes). These findings show that 2-CP can provide spinal anesthesia with similar efficacy to that of procaine for short procedures such as knee arthroscopy.

As mentioned above, procaine is considered a short-acting drug. In fact, Mulroy et al. (17) selected 75 mg of procaine with 20 µg of fentanyl as the "ideal" spinal anesthetic in a comparison among spinal, epidural, and general anesthesia for outpatient knee arthroscopy. They found that patients in the spinal group spent significantly more time in the postanesthesia care unit (146 ± 52 minutes) than those in both the epidural (92 ± 18 minutes) and general (104 ± 31 minutes) groups. Similarly, Hodgson et al. (1) showed that in outpatients undergoing knee arthroscopy, hospital discharge time after 100 mg of spinal procaine was 29 minutes longer than after 50 mg of lidocaine. Our results agree with their findings. Times to complete resolution of sensory block, ambulation, and voiding were all significantly longer in the procaine group (P = 0.0003): all subjects in the 2-CP group met simulated discharge criteria by 120 minutes, compared with 190 min in the procaine group.

One criticism of using procaine as a spinal anesthetic is its frequent incidence of side effects. In a prospective study of spinal anesthetics, Carpenter et al. (6) demonstrated that patients receiving procaine (80 ± 21 mg) had a twofold to fourfold increased risk of nausea and vomiting (31%) compared with patients receiving spinal lidocaine, tetracaine, or bupivacaine and concluded that the incidence of side effects during spinal anesthesia could be reduced by "avoiding the use of procaine in the subarachnoid space." Another shortcoming of procaine is the risk of inadequate anesthesia. In the previously mentioned study by Hodgson et al., 17% of the patients in the procaine group did not have sufficient anesthesia for the procedure, compared with only 3% in the lidocaine group (P = 0.11). Even though the incidence of TNS was significantly less in the procaine group (6% versus 31%; P = 0.007), the authors concluded that further evaluation of procaine is required before it could be recommended as a suitable alternative to lidocaine. They suggested that combining procaine with fentanyl may overcome the problems of block failure. The addition of 20 µg of fentanyl to procaine was shown to prolong motor block in one study (19), but it had no influence on either block height or the duration of sensory and motor block in another (4). However, this combination does produce frequent pruritus (19%–55%) (4,17,20). Epinephrine, another common additive to local anesthetics, does prolong sensory and motor block from procaine by 25% but is associated with a 50% incidence of nausea. Therefore, it is unclear whether additives improve the efficacy of procaine, but it is clear that they increase side effects. Interestingly, when epinephrine was combined with 2-CP, 100% of the subjects (n = 11) reported flulike symptoms (malaise, myalgias, back stiffness, and loss of appetite) (8). Likewise, when 20 µg of fentanyl was added to 2-CP, 100% of the volunteers (n = 8) experienced pruritus, whereas none did after plain 2-CP (9).

Sensory anesthesia developed in all subjects in both groups, and the lowest peak block height (L1) occurred in two subjects in the 2-CP group. The lowest peak block height in the procaine group was T9. There were no reports of nausea or vomiting, and no subject experienced symptoms consistent with TNS. However, our sample size was small and not specifically designed to have the power to detect anesthetic failures or side effects at the incidences previously described for procaine. Furthermore, large clinical trials will be necessary to ascertain its safety in clinical use.

In conclusion, we showed that spinal anesthesia after 30 mg of 2-CP, when compared directly with 80 mg of procaine, has characteristics better suited for short outpatient procedures. In agreement with procaine's producing a significantly longer tolerance to TES and higher sensory levels after 45 minutes, the satisfaction of simulated discharge criteria took an average of 50 minutes longer for these subjects. Because of this and because of previously reported more frequent incidences of block failure and nausea for procaine, 2-CP should be considered as an alternative spinal anesthetic for short outpatient surgical procedures.


   Footnotes
 
Presented in part at the American Society of Regional Anesthesia 29th Spring Meeting, Orlando, FL, March 2004.

Accepted for publication August 10, 2004.

Address correspondence to Dan J. Kopacz, MD, Department of Anesthesiology, Virginia Mason Clinic, 1100 Ninth Ave., B2-AN, Seattle, WA 98111. Address e-mail to Dan.Kopacz{at}vmmc.org. Reprints will not be available.

Although 2-chloroprocaine is approved by the Food and Drug Administration, it is not specifically indicated for spinal anesthesia. Its use for spinal anesthesia is thus considered off-label. Manufacturers of 2-chloroprocaine distinctly label the product "not for spinal anesthesia."


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press