As the trend towards ambulatory surgery continues, interest in available drugs for outpatient spinal anesthesia also increases. An ideal outpatient spinal anesthetic would provide rapid sensory and motor block, predictable regression, and an infrequent incidence of side effects. Procaine has never been commonly used because of its inconsistency and trend to produce more nausea (1,2). Despite a long history, lidocaine is currently under scrutiny because of its association with symptoms of transient neurologic syndrome (TNS) (3). Large doses of bupivacaine produce a long duration of block, risking a delay of discharge, and small doses demonstrate a large variability in block duration or require additives in addition to glucose to produce adequate surgical anesthesia (4,5).
Rapid and successful spinal anesthesia was performed with preservative-free 2-chloroprocaine in 214 patients in 1952, without side effects or toxicity (6). Though 2-chloroprocaine (commercially known as Nesacaine-CE) was used extensively for epidural anesthesia in obstetrics, its subsequent use for spinal anesthesia was abandoned when preservatives and/or the antioxidant bisulfite were added to its formulation. In fact, neurologic deficits in 8 patients (5 in obstetric patients) after unintentional intrathecal injections of large volumes of 2-chloroprocaine were reported in the 1980s (7). Symptoms of lower extremity paralysis and sacral neurological dysfunction were described, with partial to complete resolution achieved in most patients by 6–12 wk. Thorough laboratory studies consequently discovered that a combination of low pH and sodium bisulfite (the antioxidant) in the Nesacaine formulation was the cause of the neurologic injuries (8,9). A Food and Drug Administration (FDA) panel specifically convened to address this issue concluded that the drug 2-chloroprocaine itself was no more neurotoxic than lidocaine, bupivacaine, or mepivacaine (10). As 2-chloroprocaine is once again available in a preservative-free and antioxidant free form (Nesacaine-MPF, Astra Pharmaceuticals, Wilmington, DE; generic chloroprocaine, Bedford Laboratories, Bedford, OH), there is renewed interest in its use for spinal anesthesia.
Adding a small amount (0.8%–1.1%) of dextrose to spinal local anesthetics increases their baricity and produces the benefits of a faster block onset and a reduction in the variability of peak block level (11,12). However, the addition of dextrose has also been associated with an increased incidence of tourniquet pain, a reduction in the duration of lumbar/sacral analgesia, and, if a large amount of dextrose (5%–8%) is added, an extensive spread of block and accompanying hypotension (13,14). The current study specifically compares the anesthetic profile of 2-chloroprocaine spinal anesthesia performed with or without the addition of dextrose (1.1%) in healthy volunteers.
After IRB approval and informed consent were obtained, 8 healthy volunteers were enrolled in this randomized, double-blinded, crossover study. Although 2-chloroprocaine has been approved by the FDA, 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.
Each volunteer received 2 spinal anesthetics, separated by at least 1 wk, one with 40 mg preservative-free 2-chloroprocaine (2 mL, 2.0%) with 0.25 mL saline and the other with 40 mg preservative-free 2-chloroprocaine (2 mL, 2.0%) with 0.25 mL 10% dextrose. The order of administration of the spinal anesthetics was balanced and randomized (by coin flip). All volunteers had fasted for at least 6 h and voided immediately before presenting for each session. Before subarachnoid block, a 20-gauge peripheral IV catheter was inserted and lactated Ringer’s solution was administered at a rate of 8 mL/kg for the first hour, and 2 mL · kg−1 · h−1 thereafter. No sedatives were administered. Vasoactive drugs were administered only if symptoms of bradycardia or hypotension developed.
Spinal anesthesia was administered with the volunteers in the left lateral decubitus position. The skin was prepped with Betadine solution and draped in sterile fashion. After local infiltration with 1% lidocaine, the subarachnoid space was entered at the L2-3 interspace via a midline approach using a 20-gauge introducer and a 24-gauge Sprotte pencil-point needle. With the spinal needle orifice facing cephalad, 0.2 mL of cerebrospinal fluid (CSF) was aspirated, followed by injection of the study solution at a rate of 0.25 mL/s. After injection of the solution, a second 0.2-mL aspiration and reinjection of CSF were performed to confirm intrathecal administration. Subjects were immediately laid supine for the remainder of the study. The duration and quality of the block were measured using the following modalities: 1) sensory to pinprick, 2) tolerance to transcutaneous electrical stimulation (TES), 3) tolerance to thigh tourniquet, 4) motor block by electromyography (EMG) (abdomen), isometric force dynamometry (quadriceps and gastrocnemius), and modified Bromage scale (lower extremities), and 5) postvoid residual volume by ultrasound.
Sensory block to pinprick was tested bilaterally by a blinded assessor using a disposable dermatome tester every 5 min after subarachnoid injection for the first 60 min, then at 10-min intervals until recovery of pinprick sensation was demonstrated at the S2 dermatome. The forehead was used as an unblocked reference point.
Tolerance to TES was used to simulate surgical stimulation at six common surgical sites: at the lateral ankle (S1) bilaterally, at the medial aspect of the knee (L3) bilaterally, at the pubic symphysis (T12), and at the umbilicus (T10). TES was performed using a peripheral nerve stimulator with 50-Hz tetanus for 5-s duration. Stimulation was initiated at 10 mA and then increased by 10-mA increments as tolerated to a maximum of 60 mA. Previous studies have shown TES at 60 mA to be equivalent to the intensity of stimulation by surgical incision (15). TES was performed in a standardized caudad-to-cephalad manner beginning at 4 min after injection of spinal drug and then every 10 min until the subject could no longer tolerate 60 mA on 2 successive tests. If the subject was never able to tolerate 60 mA stimulation, testing of that site was terminated after 34 min.
Thirty minutes after injection of spinal drug, a thigh tourniquet was placed on the left thigh. After passive exsanguination of the leg by gravity, this cuff was inflated to 300 mm Hg. This protocol reflects the scenario of tourniquet application for lower extremity orthopedic procedures at our institution. The subjects were instructed to request removal of the tourniquet when the discomfort level became distressing to them. On request, the tourniquet was deflated and the elapsed time since inflation was recorded.
To assess abdominal muscle motor strength, a surface EMG lead was placed to the left of the umbilicus along the mid-clavicular line. Restraining straps were placed across the body at the level of the xiphoid and the ankles. The subjects were instructed to perform maximal isometric abdominal contraction against the restraining straps. Using a commercially available EMG (MyoTrac2; Thought Technology Ltd., Montreal, PQ) (surface electrodes) an average measurement (μV) 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 with plantarflexion of the foot (gastrocnemius muscle). 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. Heart rate and noninvasive blood pressure were measured at 10-min intervals.
Each subject also underwent a simulated clinical discharge pathway. On recovery of S2 dermatome to pinprick, the subjects attempted ambulation without assistance. If ambulation was successful pre-void bladder volume was assessed using a commercially available bladder ultrasound (Bladderscan BV12500; Diagnostic Ultrasound Corporation, Kirkland, WA) in triplicate and the mean value was recorded. The subjects then attempted to void. If either ambulation or voiding were unsuccessful, then the attempts were repeated at 15-min intervals until these end-points were achieved. After a successful void, bladder ultrasound was repeated in triplicate and the mean post-void residual volume was recorded. Volunteers were questioned daily for 72 h regarding the presence of headache, backache (quality and radiation), or other residual symptoms.
The sample size of 8 subjects was calculated to detect a difference in time to complete regression of sensory anesthesia of 15 min (approximately 20%) with a standard deviation of 10 min using an α of 0.05 and a β of 0.2. Differences in peak dermatomal block heights, duration of sensory and motor block, tolerance of tourniquet and TES at 60 mA, ability to ambulate and void, and post-void residual volumes were analyzed using paired Student’s t-tests and repeated-measures analysis of variance. Significance was considered P < 0.05. Results are reported as mean ± sd.
Spinal anesthesia was successful in all subjects (5 male, 3 female). Subject ages ranged from 21 to 48 (37 ± 10) yr, heights from 155–185 (170 ± 11) cm, and weights from 61–114 (78 ± 16) kg. No subject required vasoactive medications. One subject received more IV fluid than allowed by protocol, so their time to void and bladder volume data for both anesthetics were excluded. No subject reported signs of TNS or neurotoxicity.
Complete regression of the block occurred within 110 min in all subjects (range, 80–110 min). There was no statistically significant difference in peak height (Fig. 1), time to achieve peak block height, time for 2-segment regression, regression to L1, tolerance of tourniquet (Table 1), or return of motor function (Fig. 2). Tolerance of TES of right (non-dependent) L3 with dextrose was 65 ± 18 min, and it was 74 ± 15 min with saline (P = 0.02). Tolerance to TES at all other dermatomes was not significantly different. Time to ambulate and void was not significantly different. However, post-void residual volumes were significantly larger in the dextrose group (Fig. 3), with a mean post-void residual bladder volume for the dextrose group of 74 ± 67 mL versus 16 ± 35 mL for the saline group (P = 0.02). Changes in heart rate and blood pressure were similar between groups (Fig. 4).
This study shows that spinal anesthesia with 40 mg of preservative-free 2-chloroprocaine, both plain and in 1.1% dextrose, provides reliable surgical anesthesia with predictable regression. However, no significant differences in peak dermatomal height, time for 2-segment regression, regression to L1, tolerance of tourniquet, or return of motor function were found between the plain and dextrose groups.
Though 2-chloroprocaine (commercially known as Nesacaine-CE) was used extensively for epidural anesthesia in obstetrics, its subsequent use for spinal anesthesia was abandoned when preservatives and/or the antioxidant bisulfite were added to its formulation. One commercially available preparation of 2-chloroprocaine still contains a large concentration of bisulfite (Abbott Laboratories, North Chicago, IL; bisulfite 1.8 mg/mL) and should not be used for spinal anesthesia, as this formulation may be neurotoxic. This bisulfite-containing preparation is packaged in a clear vial, distinguishing it from the bisulfite-free preparations (Nesacaine-MPF, Astra Pharmaceuticals; generic chloroprocaine, Bedford Laboratories), which are both packaged in a brown vial to prevent photodegradation. Both of these bisulfite-free preparations have been safely used for spinal anesthesia without side effects.
Several studies have looked at differing concentrations of dextrose in local anesthetic solutions for spinal anesthesia in both pregnant and nonpregnant patients (11,12,16,17). These studies suggest that smaller concentrations of dextrose (0.5%–1%) were as effective as larger concentrations (5%–10%) in producing reliable spinal anesthesia, with distribution characteristic of hyperbaric solutions. There is some evidence that use of larger concentrations of dextrose increases cephalad spread of drug and the risk of blockade of cardioaccelerator fibers (12,14). We chose a concentration of 1.1% dextrose based on these previous studies and ease of preparation.
Among the many factors that affect the spread of a solution administered intrathecally, baricity is one that is often manipulated by the anesthesiologist. The most commonly used method of increasing the density of anesthetic solutions is the addition of dextrose. Hyperbaric solutions tend to have greater cephalad spread in a supine patient, which is thought to be secondary to gravitational movement of the anesthetic solution to the most dependent region of the thoracic curvature. Na and Kopacz (18) recently defined the lower limit of hyperbaricity as 1.00100 g/mL based on previous measurements of the density of human CSF (19). They also measured the density of plain preservative-free 2-chloroprocaine as 1.00123 g/mL, marginally hyperbaric. The addition of dextrose 1.1% to this solution produces a definitively hyperbaric solution (density >1.00300 g/mL). Our results show that preservative-free 2-chloroprocaine has a density adequate to clinically behave in a hyperbaric fashion in healthy subjects in the supine position, producing and average peak block height of T3–4. It is conceivable that these two study solutions may produce quite different clinical effects in patients in whom spinal anesthesia is performed in the sitting position.
The mechanism of tourniquet pain is poorly understood. There is some evidence that onset of tourniquet pain may have little to do with pinprick sensory level (13,20). Several theories have been devised to explain this finding. Bridenbaugh et al. (13) reported that the addition of dextrose to bupivacaine for spinal anesthesia was associated with an increased incidence of tourniquet pain compared to plain bupivacaine. We were unable to demonstrate any difference in tolerance of thigh tourniquet when dextrose was added to 2-chloroprocaine for spinal anesthesia.
One of the principal concerns in using spinal anesthesia for outpatient surgical procedures is the potential delay of discharge because of inability to void. Although the addition of dextrose to 2-chloroprocaine for spinal anesthesia does not significantly alter the clinical characteristics of sensory or motor block, adding dextrose to this drug increased the degree of residual bladder dysfunction. We used post-void residual volume as an indirect assessment of detrusor muscle function and the risk of postoperative urinary retention (21,22). We showed increased post-void residual volumes in the dextrose group compared with plain. This effect is thought to be attributable to a baricity-determined distribution of 2-chloroprocaine within the intrathecal space rather than a direct pharmacodynamic action of dextrose itself. Although these values were statistically significant, it is uncertain if this finding has any clinical significance. The time to void and thus achieve discharge criteria was similar with or without dextrose. Outpatients undergoing low-risk procedures using short-acting spinal anesthetics may not need to demonstrate the ability to void before discharge (23). The impact of our findings may only surface in patients with baseline voiding difficulties and/or undergoing high-risk procedures, such as inguinal herniorrhaphy or hemorrhoidectomy. However, as no distinct advantages in adding dextrose to 2-chloroprocaine were found, we are not compelled to expose patients to this theoretical risk.
In summary, spinal anesthesia with 2-chloroprocaine provides adequate potency and reliable regression, hence making it an attractive option for outpatient surgery. As the number of subjects in this initial study is quite small, large-scale clinical trials are underway to further delineate the safety and efficacy of spinal 2-chloroprocaine. This study demonstrates that the addition of dextrose does not alter peak block height or tolerance of thigh tourniquet and increases the degree of residual bladder dysfunction. Therefore, the addition of glucose to 2-chloroprocaine for spinal anesthesia is not necessary or recommended. Spinal anesthesia with 2-chloroprocaine is achieved seemingly without the concerns of TNS that have caused lidocaine to fall out of favor.
1. Hodgson PS, Liu SS, Batra MS, et al. Procaine compared with lidocaine for incidence of transient neurologic symptoms. Reg Anesth Pain Med 2000; 25: 218–22.
2. Le Truong HH, Girard M, Drolet P, et al. Spinal anesthesia: a comparison of procaine and lidocaine. Can J Anaesth 2001; 48: 470–3.
3. Pollock JE. Transient neurologic symptoms: etiology, risk factors, and management. Reg Anesth Pain Med 2002; 27: 581–6.
4. Ben-David B, Solomon E, Admoni H, et al. Intrathecal fentanyl with small-dose dilute bupivacaine: better anesthesia without prolonging recovery. Anesth Analg 1997; 85: 560–5.
5. Liu SS, Ware PD, Allen HW, et al. Dose-response characteristics of spinal bupivacaine in volunteers: clinical implications for ambulatory anesthesia. Anesthesiology 1996; 85: 729–36.
6. Foldes FF, McNall PG. 2-chloroprocaine: a new local anesthetic agent. Anesthesiology 1952; 13: 287–96.
7. Winnie AP, Nadar AM. Santayana’s prophecy fulfilled. Reg Anesth Pain Med 2001; 26: 558–64.
8. Wang BC, Hillman DE, Spielholz NI. Chronic neurological deficits and Nesacaine-CE: an effect of the anesthetic, 2-chloroprocaine, or the antioxidant, sodium bisulfite? Anesth Analg 1984; 63: 445–7.
9. Gissen AJ, Datta S, Lambert D. The chloroprocaine controversy II: is chloroprocaine neurotoxic? Reg Anesth 1984; 9: 135–45.
10. Scally DL. Review and evaluation of clinical data: special summary of adverse experiences for review by Food and Drug Administration Anesthetic Life Support Drug Advisory Committee, 1980.
11. Bannister J, McClure JH, Wildsmith JAW. Effect of glucose concentration on the intrathecal spread of 0.5% bupivacaine. Br J Anaesth 1990; 64: 232–4.
12. Sanderson P, Read J, Littlewood DG, et al. Interaction between baricity (glucose concentration) and other factors influencing intrathecal spread. Br J Anaesth 1994; 73: 744–6.
13. Bridenbaugh PO, Hagenouw RPM, Gielen MJM, Edstrom HH. Addition of glucose to bupivacaine in spinal anesthesia increases incidence of tourniquet pain. Anesth Analg 1986; 65: 1181–5.
14. Chambers WA, Edstrom HH, Scott DB. Effect of baricity on spinal anaesthesia with bupivacaine. Br J Anaesth 1981; 53: 279–82.
15. Petersen-Felix S, Zbinden AM, Fischer M, et al. Isoflurane minimum alveolar concentration decreases during anesthesia and surgery. Anesthesiology 1993; 79: 959–65.
16. Connolly C, McLeod GA, Wildsmith JA. Spinal anesthesia for Caesarean section with bupivacaine 5 mg mL−1
in glucose 8 or 80 mg mL−1
. Br J Anaesth 2001; 86: 805–7.
17. Whiteside JB, Burke D, Wildsmith JAW. Spinal anaesthesia with ropivacaine 5 mg ml−1
in glucose 10 mg mL−1
or 50 mg mL−1
. Br J Anaesth 1001; 86: 241–4.
18. Na KB, Kopacz DJ. Spinal chloroprocaine solutions: Density at 37°C and pH titration. Anesth Analg 2003; 97: 70–4.
19. Richardson MG, Wissler RN. Density of lumbar cerebrospinal fluid in pregnant and nonpregnant humans. Anesthesiology 1996; 85: 326–30.
20. Concepcion MA, Lambert DH, Welch KA, Covino BG. Tourniquet pain during spinal anesthesia: a comparison of plain solutions of tetracaine and bupivacaine. Anesth Analg 1988; 67: 828–32.
21. Barrington JW, Edwards G, Ashcroft M, Adecanmi O. Measurement of bladder volume following Cesarean section using Bladderscan. Int Urogyn J 2001; 12: 373–4.
22. Roseland LA, Stubhaug A, Breivik H. Detecting postoperative urinary retention with an ultrasound scanner. Acta Anaesthesiol Scand 2002; 46: 279–82.
© 2004 International Anesthesia Research Society
23. Mulroy MF, Salinas FV, Larkin KL, Polissar NL. Ambulatory surgery patients may be discharged before voiding after short-acting spinal and epidural anesthesia. Anesthesiology 2002; 97: 315–9.