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Anesth Analg 2005;100:559-565 © 2005 International Anesthesia Research Society doi: 10.1213/01.ANE.0000143381.30409.62
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Abstract |
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Preservative-free 2-chloroprocaine (2-CP) is being investigated for short-acting spinal anesthesia. Clonidine improves the quality of spinal bupivacaine and ropivacaine, but in traditional doses (1–2 µg/kg) it produces systemic side effects. It has not been studied in combination with 2-CP. In this double-blind, randomized crossover study, we compared spinal 2-CP (30 mg) with and without clonidine (15 µg) in eight volunteers. Pinprick anesthesia, motor strength, tolerance to electrical stimulation and thigh tourniquet, and time to ambulation were assessed. Peak block height was similar between 2-CP (T8 [range, T6 to L2]) and 2-CP with clonidine (T8 [range, T4 to T11]) (P = 0.57). Sensory anesthesia was prolonged with clonidine at L1 (51 ± 23 min versus 76 ± 11 min; P = 0.002), as was complete block regression (99 ± 18 min versus 131 ± 15 min; P = 0.001). Lower extremity motor blockade was increased with clonidine (return to baseline Bromage score: 65 ± 13 min versus 79 ± 19 min, P = 0.004; return to 90% gastrocnemius strength: P = 0.003). Clonidine increased tourniquet tolerance from 33 to 45 min (P = 0.06) and increased time to ambulation, spontaneous voiding, and discharge (99 ± 18 min versus 131 ± 15 min for all; P = 0.001). There were no differences in hemodynamic measurements, and no subject reported transient neurologic symptoms. We conclude that small-dose clonidine increases the duration and improves the quality of 2-CP spinal anesthesia without systemic side effects.
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Introduction |
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In 1952, Foldes and McNall (1) first described 2-chloroprocaine (2-CP) spinal anesthesia in 214 patients without neurologic complications. 2-CP was used extensively over the next three decades for epidural anesthesia because of its fast onset time, short duration of action, and small potential for systemic toxicity. From 1980 to 1982, nine patients were found to have persistent motor, sensory, or sphincter function deficits after injection of large volumes of epidural 2-CP (2–4). Four of the nine patients were known to have accidental intrathecal injections. The formulation of 2-CP used at that time (Nesacaine-CE) contained 0.2% sodium bisulfite as an antioxidant.
Wang et al. (5) and Gissen et al. (6) determined that the combination with sodium bisulfite at a low pH was the cause of the persistent neurologic deficits, although recent studies have disputed their conclusions (7,8). Sodium bisulfite was subsequently removed from most 2-CP preparations, but it is again being used for spinal anesthesia in surgical patients (9,10).
Lidocaine has been under scrutiny as a spinal anesthetic for outpatients since Schneider et al. (11) reported patient complaints of pain radiating to the buttocks and lower extremities after receiving subarachnoid lidocaine. This phenomenon, called "transient neurologic symptoms" (TNS), is most often seen with lidocaine; outpatient surgery and surgery in the lithotomy position are two other primary risk factors (12). Several studies have found preservative-free 2-CP to be a suitable alternative to lidocaine for spinal anesthesia, without signs or symptoms of neurologic impairment or TNS (13–15).
The addition of adjuncts to local anesthetics has been used to improve the quality of spinal anesthesia. Clonidine, an 
2-adrenergic agonist, prolongs both the sensory and motor blockade produced by spinal lidocaine, bupivacaine, and ropivacaine (16–20). Intrathecal clonidine has traditionally been used in doses larger than 100 µg and has been associated with hypotension, bradycardia, and sedation. However, doses of clonidine as small as 15 µg have been shown to improve the quality of ropivacaine (17) and bupivacaine (19) spinal anesthesia without producing these systemic effects.
Clonidine has not been studied in conjunction with spinal 2-CP. The aim of this study was to evaluate whether adding small-dose clonidine changes the duration of spinal anesthesia, independently alters either sensory or motor blockade, or has no effect on subarachnoid 2-CP in a volunteer model.
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Methods |
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After IRB approval and written informed consent, eight healthy volunteers were enrolled in this randomized, double-blind, crossover study. All subjects were made aware in their consent that the 2-CP manufacturing label specifically states "not for spinal anesthesia." All participants received two spinal anesthetics separated by at least 48 h. One spinal anesthetic contained 2-CP (30 mg; 1.5 mL of 2.0%) with 15 µg of clonidine (0.15 mL), and the other contained 2-CP (30 mg) with saline (0.15 mL) in a comparable volume (total volume, 1.65 mL). A commercially available preservative- and bisulfite-free formulation of 2-CP (Nesacaine-MPF; AstraZeneca Pharmaceuticals, Worchester, MA) was used in this study, and because the long-term stability of 2-CP and clonidine is unknown, solutions were prepared immediately before injection. A random-number generator was used to determine the order of drug administration. All subjects received nothing by mouth for more than 6 h for solids and 2 h for liquids and were instructed to void before each session. A 20-gauge peripheral IV catheter was placed, and lactated Ringer's solution was administered at 8 mL/kg for the first hour and 2 mL/kg thereafter. No sedatives were used during the study.
Each volunteer was placed in the left lateral decubitus position, and the L2-3 interspace was prepared and draped in a sterile fashion. By using a midline approach, the subarachnoid space was entered by using a 24-gauge Sprotte needle with the orifice facing cephalad. Cerebrospinal fluid (CSF) 0.2 mL was withdrawn before injection of the study drug to confirm needle placement. The study solution was then injected, and after completion, 0.2 mL of CSF was again aspirated and reinjected to confirm placement. Subjects were immediately placed supine for the remainder of the study.
Vital signs were monitored, including noninvasive blood pressure, pulse oximetry, and electrocardiogram. Arterial blood pressure and heart rate were recorded at baseline and then every 5 min thereafter. Sensory anesthesia was assessed with pinprick by using the lateral forearm as a control. Measurements were made every 5 min for the first 60 min and then every 10 min until regression to the S2 dermatome.
Transcutaneous electrical stimulation (TES) was used to simulate surgical stimulation and was tested at six sites: lateral ankle bilaterally (S1), medial knee bilaterally (L3), midline pubis (T12), and umbilicus (T10). TES was performed with a peripheral nerve stimulator (Model NSS25; Fisher and Paykel, Auckland, New Zealand) by using a 50-Hz tetanus for 5 s. This was initially tested at 10 mA and was increased by 10 mA to a maximum of 60 mA according to subject tolerance. The maximum limit of 60 mA was used in this study because previous studies have shown TES at 60 mA to be comparable to the intensity of stimulation caused by surgical skin incision (21). TES was tested in a caudad to cephalad fashion and was performed 4 min after spinal anesthetic administration and then every 10 min until 2 consecutive measurements of <60 mA were obtained. If tolerance to 60 mA was never obtained, testing was continued for at least 34 min at that site.
Thirty minutes after spinal administration, a 34-in. tourniquet was placed on the left thigh. The leg was passively exsanguinated by gravity, and the tourniquet was inflated to 300 mm Hg. Subjects were instructed to request removal of the tourniquet when they believed that they would need supplemental analgesia to tolerate it any longer.
Muscle strength of the right lower extremity was measured by using a commercially available isometric force dynamometer (Micro FET; Hoggan Health Industries, Draper, UT). This was performed during a 5-s maximal force contraction of the right gastrocnemius (plantar flexion against resistance) and the right quadriceps muscle (straight leg lift against resistance). Measurements were repeated three times and averaged. They were measured first at baseline and then at 10-min intervals after injection until >90% of baseline strength returned. The ability to move the lower extremities was assessed by using a modified Bromage scale (0 = no block, 1 = able to bend the knee, 2 = able to dorsiflex the foot, and 3 = complete motor block) and was recorded every 10 min until resolution of motor blockade.
Each subject also underwent a simulated discharge pathway. Once recovery of the S2 dermatome occurred, prevoid bladder volumes were recorded with a commercially available bladder ultrasound machine. The subjects then attempted to ambulate without assistance, and if successful, they were instructed to void. Postvoid residual bladder volume was remeasured with the bladder ultrasound machine. 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 they were recontacted after 6 mo for long-term follow-up.
By using a difference of 15 min to complete sensory resolution, an sd of 10 min, and an = 0.05 with ß = 0.80, 8 subjects were required. Peak block height comparisons were made with the Mann-Whitney U-test. Comparisons of dermatome regression over time, isometric force dynamometry, and hemodynamic data were made with repeated-measures analysis of variance with Bonferroni-Dunn tests for post hoc analysis. Paired Student's t-tests were used to determine differences between anesthetics for all other measurements. Unless otherwise stated, data are mean ± sd, and significance was defined as P < 0.05.
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Results |
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Successful spinal anesthesia was obtained in all subjects (four men and four women). Subjects' ages ranged from 27 to 60 yr (34 ± 11 [sd] yr), height from 157 to 183 cm (171 ± 8 [sd] cm), and weight from 54 to 93 kg (74 ± 17 [sd] kg). Sensory and motor block characteristics are described in Table 1.
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With the addition of clonidine, sensory anesthesia was significantly prolonged as measured by regression to L1 and complete sensory regression (Fig. 1, Table 1). Tolerance to the thigh tourniquet was prolonged with the addition of clonidine, but this did not reach statistical significance (P = 0.0571; Fig. 2). Motor blockade, measured by the return of lower extremity movement according to modified Bromage scores (Table 1) and time for the return of gastrocnemius muscle strength (Fig. 3, Table 1), was significantly prolonged. Although the addition of clonidine improved the quality of quadriceps muscle blockade (Fig. 4), the time to complete recovery of quadriceps strength was unaffected (Table 1). Peak block height was not affected by the addition of clonidine (Fig. 1, Table 1). Times to two-segment regression and TES to the T12 and T10 dermatomes, as well as the right (nondependent) S1 dermatome, were also not significantly different between groups (Table 1). Tolerance to TES at the L3 dermatomes bilaterally and the left (dependent) S1 dermatome was prolonged significantly with the addition of clonidine. One subject achieved a peak block height of only L2, and two subjects experienced sacral sparing with 2-CP 30 mg alone. This was not seen with the addition of clonidine.
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Baseline heart rate and arterial blood pressure measurements for both groups were similar, and, as expected with spinal anesthesia, there was a significant decrease in both heart rate and arterial blood pressure from baseline with the administration of spinal 2-CP with and without clonidine. However, there were no significant differences in the change in heart rate or arterial blood pressure when comparing spinal 2-CP alone and spinal 2-CP with clonidine (P = 0.69 and 0.57, respectively). One subject in the clonidine group required ephedrine 5 mg for a symptomatic systolic blood pressure of 83 mm Hg ("queasy," block height T4 bilaterally). No further vasopressors were required.
All subjects were able to ambulate and void successfully after the return of sensation to the S2 dermatome, but there was a significant increase in the time to ambulate and void with the addition of clonidine (P = 0.0009; Fig. 2). There was no significant difference in postvoid residual bladder volumes between groups (P > 0.05). One subject reported feeling tired during the session after the injection of clonidine, but no residual effects were noted, and discharge was not delayed. No other reports of sedation were noted in either group. No subject 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 of follow-up.
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Discussion |
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This study demonstrates that 30 mg of preservative-free 2-CP alone produces adequate spinal anesthesia for outpatient surgical procedures of the lower extremities and that the addition of 15 µg of clonidine prolongs and improves both sensory and motor blockade. Block regression to L1 was increased by 25 minutes and complete regression by 31 minutes in the groups that received clonidine as an adjunct. Previous studies combining 15 µg of clonidine with bupivacaine (19) and ropivacaine (17) demonstrated increased block height compared with each drug alone. In contrast, in our study, the addition of small-dose clonidine did not increase the peak block of 2-CP spinal anesthesia. Several measurements were used to evaluate the return of motor function. These included the modified Bromage scale and isometric force dynamometry of the quadriceps and gastrocnemius muscles. All tests showed a significant prolongation of motor blockade with the addition of clonidine, except for the time to return of quadriceps strength. This motor block prolongation coincides with the prolongation of sensory anesthesia.
Intrathecal clonidine has been shown to improve the quality of spinal anesthesia, but in doses of 1–2 µg/kg, significant systemic side effects were seen, including sedation, hypotension, and bradycardia (16,18,20). Recent studies have evaluated the effects of clonidine in doses as small as 15 µg and have found it to be effective and without these unwanted side effects (17,19). Our findings were consistent with these studies in that there was no significant difference between groups with regard to changes in systolic blood pressure and heart rate. Although this study was conducted in young healthy volunteers, the previous studies were in patients of all ages. One subject did report feeling tired, starting approximately 30 minutes after injection, during the session with intrathecal clonidine. These symptoms resolved with complete regression of spinal anesthesia, and the attainment of discharge criteria was not delayed.
Although the addition of fentanyl and clonidine to spinal 2-CP has not been directly studied, a previous study investigating the addition of fentanyl (20 µg) with identical methods showed an increased duration of sensory anesthesia, comparable to what was shown for the addition of clonidine in the current study (15). Unlike clonidine, the addition of fentanyl also increased peak block height by 2 dermatomes and produced frequent (7 of 8 subjects) pruritus.
The significant increase in time to ambulation and voiding with added clonidine was simply related to the longer duration of anesthesia. Once the block regressed to S2, all subjects receiving 2-CP with clonidine were able to immediately ambulate without assistance and to spontaneously void without difficulty.
Eight cases of neurotoxicity were reported in the 1980s, after the accidental intrathecal injection of large amounts of bisulfite-containing CP (Nesacaine-CE) (2–4). Although the CP currently being used for spinal anesthesia is bisulfite free and the dose is 10-fold less than the amount injected in these previous cases, the use of 2-CP for spinal anesthesia is controversial. When evaluating animal studies investigating this issue, one finds numerous methodological differences (2-CP dose, volume, and concentration; bisulfite dose and concentration; animal species used; duration of drug exposure; peripheral nerve versus spinal injection; and spinal catheter/infusion versus single injection).
Some studies have looked only at 2-CP with sodium bisulfite and have found conflicting results. Barsa et al. (22), in a rabbit vagus nerve model, found 3% 2-CP with bisulfite to be neurotoxic. Ford and Raj (23), in a cat saphenous nerve model, found 3% 2-CP with bisulfite not to be neurotoxic and found bisulfite itself to be neurotoxic only when the concentration was increased to 1.2% or more. In four studies in which "clinically equivalent" spinal injections of bisulfite-free 2-CP were administered, no toxicity was found (5,24–26). However, Rosen et al. (27) found that when large-volume spinal injections were given to simulate the accidental subarachnoid injection of an epidural dose of local anesthetic solution, 3% 2-CP could produce neurotoxicity. However, it was no more likely with 2-CP than with either 2% lidocaine or 0.75% bupivacaine. Similarly, Li et al. (28) found no difference in the incidence of neurotoxicity among 2-CP, lidocaine, and bupivacaine in a rat subarachnoid infusion model. Kalichman et al. (7), in a rat sciatic nerve model, found that 3% 2-CP caused neurotoxicity but that plain bisulfite did not. A similar study from the same group (29) found that the ability of 2-CP to cause neurotoxicity was equivalent to that of tetracaine, another ester local anesthetic used extensively for spinal anesthesia. Perhaps most confusing is a recent rat study by Taniguchi et al. (8), in which bisulfite alone was not neurotoxic when given by slow spinal infusion and may actually have lessened the toxicity produced by 3% 2-CP. This salutary effect of bisulfite has not been investigated for neurotoxicity induced by other local anesthetics.
CP 30 and 40 mg have been the most common doses used in more than 600 surgical outpatients recently reported (9,10). Forty milligrams of 2-CP has been shown to produce effective spinal anesthesia with a predictable, short duration of action in previous volunteer studies (14,15). We chose to study the effects of a smaller dose of 2-CP (30 mg) and found that it also produces adequate anesthesia. However, one subject achieved a peak block height of only L2, and 2 subjects experienced sacral sparing with 2-CP 30 mg alone: this was not seen in the previous reports with 40 mg. This was also not seen with the addition of clonidine to 30 mg of 2-CP.
In conclusion, small-dose clonidine increases the duration and improves the quality of both sensory and motor blockade when added to 2-CP spinal anesthesia. By using a dose of 15 µg, we did not observe the unwanted side effects seen with the traditional larger doses. Although the duration of motor blockade is prolonged with the adjunct clonidine, the mean total time to ambulate and void was only 131 minutes. This makes it a suitable combination for outpatient anesthesia.
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Footnotes |
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Presented in part at the American Society of Regional Anesthesia 29th Spring Meeting, Orlando, FL, March 2004.
Although 2-chloroprocaine is 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 in their written informed consent.
Accepted for publication August 10, 2004.
Address correspondence to Dan J. Kopacz, MD, Department of Anesthesiology, Virginia Mason Clinic, 1100 Ninth Ave., B2-AN, PO Box 900, Seattle, WA 98111. Address e-mail to Dan.Kopacz{at}vmmc.org. Reprints will not be available from the authors.
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References |
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- Foldes F, McNall P. 2-Chloroprocaine: a new local anesthetic agent. Anesthesiology 1952;13:287–96.[Web of Science][Medline]
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[Free Full Text] - Wang BC, Hillman DE, Spielholz NI, Turndorf H. Chronic neurological deficits and Nesacaine-CE: an effect of the anesthetic, 2-chloroprocaine, or the antioxidant, sodium bisulfite? Anesth Analg 1984;63:445–7.
[Abstract/Free Full Text] - Gissen A, Datta S, Lambert D. The chloroprocaine controversy. Reg Anesth Pain Med 1984;9:124–45.
- Kalichman M, Powell H, Reisner LS, Myers R. The role of 2-chloroprocaine and sodium bisulfite in rat sciatic nerve edema. J Neuropathol Exp Neurol 1986;45:566–75.[Web of Science][Medline]
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- Schneider M, Ettlin T, Kaufmann M, et al. Transient neurologic toxicity after hyperbaric subarachnoid anesthesia with 5% lidocaine. Anesth Analg 1993;76:1154–7.
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[Abstract/Free Full Text] - Vath J, Kopacz D. Spinal 2-chloroprocaine: the effect of added fentanyl. Anesth Analg 2004;98:89–94.
[Abstract/Free Full Text] - Bonnet F, Brun Buisson V, Francois Y, et al. Effects of oral and subarachnoid clonidine on spinal anesthesia with bupivacaine. Reg Anesth Pain Med 1990;15:211–4.
- De Kock M, Gautier P, Fanard L, et al. Intrathecal ropivacaine and clonidine for ambulatory knee arthroscopy. Anesthesiology 2001;94:574–8.[Web of Science][Medline]
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[Abstract/Free Full Text] - Niemi L. Effects of intrathecal clonidine on duration of bupivacaine spinal anaesthesia, haemodynamics, and postoperative analgesia in patients undergoing knee arthroscopy. Acta Anaesthesiol Scand 1994;38:724–8.[Web of Science][Medline]
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