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From the University of Parma, Department of Anesthesia and Pain Therapy, Ospedale Maggiore di Parma, Parma, Italy.
Address correspondence and reprint requests to Andrea Casati, MD, Department of Anesthesiology, Azienda Ospedaliera di Parma, Via Gramsci 14 – 43100 Parma, Italy. Address e-mail to acasati{at}ao.pr.it.
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Abstract |
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 Top Abstract IntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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Introduction |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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2-chlororprocaine is an amino-ester local anesthetic with a very short half-life and a potentially favorable profile for short procedures (8), but concerns for neurotoxicity emerged two decades ago with eight cases of neurologic injury associated with the use of a chloroprocaine solution containing the antioxidant sodium-bisulfite (9–11). Several studies have evaluated the neurotoxic potential of chloroprocaine and bisulfite in different experimental models, reporting conflicting results (12–15). These different findings are likely related to the differences in the relative dosing of chloroprocaine and bisulfite and the susceptibility of the various model systems to sulfur dioxide because of the disparity in levels or activity of the sulfite oxidase enzyme in the different mammalian species (16). However, even though further data are required to better evaluate the toxicity potential of chloroprocaine, rigorous investigations in volunteers (17–19) and clinical reports on off-label use of this drug in daily practice (20,21) support the safety profile of intrathecal chloroprocaine.
Volunteer studies suggested that doses of 2-chloroprocaine ranging between 30 and 60 mg could be indicated in an outpatient setting (17–19). However, few studies in outpatients have evaluated spinal anesthesia with 2-chloroprocaine in a clinical setting of day-case surgery. We, therefore, conducted this prospective, randomized, double-blind study to evaluate the adequacy of 3 doses of 1% 2-chloroprocaine (30, 40, and 50 mg) for outpatient lower limb surgery lasting 30 to 60 min and to determine the recovery profile of these 3 different doses.
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METHODS |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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After arrival in the operating room an 18-gauge IV catheter was placed at the forearm, and 7 mL/kg of Ringer’s lactate solution was infused over a 20-min period. Standard premedication was given (midazolam 0.03 mg/kg IV). Standard monitoring was used throughout the procedure, including noninvasive arterial blood pressure, heart rate, and pulse-oximetry.
Spinal anesthesia was performed at the L3–4 or L4–5 interspaces with the patient sitting, using the midline approach and a 25-gauge Whitacre spinal needle (Becton Dickinson, Franklin Lakes, NJ). Using a computer-generated sequence of random numbers and a sealed envelope technique, patients were randomly allocated to 1 of 3 groups receiving intrathecal injection of, respectively, 30 mg (group Chlor-30, n = 15), 40 mg (group Chlor-40, n = 15), or 50 mg (group Chlor-50, n = 15) of 1% plain 2-chloroprocaine (Sintetica, Mendrisio, Switzerland).
After completing spinal injection, patients were placed supine, while an independent observer blinded as to patient grouping evaluated sensory and motor blocks every 3 min until readiness to surgery, then every 5 min until the maximum level of sensory block was reached (the same level of sensory block for three consecutive observations). Further assessments were performed every 15 min for the first 60 min and then every 30 min until fulfillment of home discharge criteria. At the same observation times systolic and diastolic arterial blood pressure values and heart rate were also recorded. The level of sensory block was assessed using the loss of pinprick sensation (20-gauge hypodermic needle); whereas motor block was assessed using the modified Bromage scale (0 = no motor block, 1 = hip blocked, 2 = hip and knee blocked, 3 = hip, knee, and ankle blocked). Readiness to surgery was defined as loss of pinprick sensation 
T10, with a modified Bromage score 2.
After surgical anesthesia was achieved, the procedure began. The blinded observer also evaluated sensory and motor functions during the procedure on the non-operative side. If the patient complained of pain during surgery, supplemental analgesia with 0.1 mg fentanyl IV was administered. If this was not adequate to complete surgery, general anesthesia was provided.
Clinically relevant hypotension (defined as a decrease in systolic arterial blood pressure 30% from baseline values) was initially treated with a rapid IV infusion of 200 mL of Ringer’s lactate solution over a 10-min period. If this was not effective, 5 mg ephedrine IV was administered. Occurrence of clinically relevant bradycardia (defined as heart rate reduction 
45 bpm) was treated with 0.5 mg atropine IV.
Postoperative analgesia consisted of ketoprofen 50 mg per os every 8 h starting from the day of surgery; rescue analgesia with oral tramadol (50 mg) was administered if requested and the need was recorded.
Times from the end of the spinal injection to readiness to surgery (onset time), as well as the maximum level of sensory block, time for complete regression of spinal block, voiding, unassisted ambulation and eligibility for home discharge were also recorded. Criteria for home discharge were as follows: stable vital signs, able to tolerate liquids by mouth, walk with crutches and void, with no nausea or pain (22). Effective anesthesia was defined as the presence of adequate sensory and motor blocks as defined above with a duration adequate to cover surgery.
The occurrence of transient neurologic symptoms was assessed 24 h and 7 days after surgery using a standardized telephone call questionnaire (1–5) asking patients about the presence of headache, back pain, inability to void, or presence of residual paresthesia/dysesthesia in the lower limbs or buttocks.
To calculate the required study size we considered a 15-min reduction in the time required for complete regression of spinal block among the three considered doses of 2-chlorprocaine as clinically relevant. Based on the standard deviation reported in previous investigations (17–19) and considering an effect size to standard deviation ratio (E/S) ranging between 0.95 and 1.3, 11 to 15 patients per group were required to detect the designed difference in complete regression of spinal block, accepting a two-tailed 
error of 5% and a ß error of 20% (23).
Statistical analysis was performed using the Systat 7.0 statistical software package (SPSS Inc., Chicago, IL). Normal distribution of the collected data was first evaluated using the Kolmogorov-Smirnov test. Continuous variables were analyzed using the analysis of variance or the Kruskal-Wallis test according to data distribution. The Tukey test or the Mann-Whitney U-test with Bonferroni correction for multiple comparisons were used for post hoc analysis. A two-way analysis of variance for repeated measures was used to analyze changes over time of continuous variables. Categorical variables were analyzed using the contingency tables analysis and the 
2 test with the appropriate corrections. For statistical analysis of the evolution of sensory block each dermatome above S3 was assigned an integer (i.e., S2 = 1, L1 = 7, T10 = 10; T8 = 12, and so on). Continuous variables are presented as mean ± sd or median (range) according to data distribution; categorical data are presented as number (%). A P value 0.05 was considered significant.
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RESULTS |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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The median (range) time required to achieve readiness to surgery was 8 (3–25) min in group Chlor-30, 7 (3–26) min in group Chlor-40, and 6 (3–20) min in group Chlor-50 (P = 0.74).
Spinal anesthesia was successful in all patients, and in no case was general anesthesia required to complete surgery. The median (range) maximum level of sensory block was T9 (T12–4) in group Chlor-30, T9 (T12–6) in group Chlor-40, and T9 (T12–7) in group Chlor-50 (P = 0.388). Intraoperative analgesic supplementation was required for 7 patients (50%) of group Chlor-30, 5 patients (33%) of group Chlor-40, and 2 patients (13%) of group Chlor-50 (P = 0.09). In 7 of these 14 patients (5 in group Chlor-30 [35%] and 2 in group Chlor-40 [13%]) analgesic supplementation was required on completion of the procedure because of insufficient duration of spinal block (P = 0.014). These 7 patients required analgesic implementation after 40 (30–60) min and were considered as spinal block inadequate for the designed surgical procedure.
Clinically relevant hypotension requiring rapid IV intravascular fluid infusion or ephedrine administration was not observed in any patient throughout the study; 5 patients in group Chlor-30 only (38%) required IV atropine because of bradycardia (P = 0.001).
The recovery profile of sensory block was faster in patients of group Chlor-30 than in groups Chlor-40 and Chlor-50 (P = 0.001) (Figs. 1 and 2).
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Postoperative analgesia was adequate in all patients, and only one patient in group Chlor-30 required rescue tramadol during the first 24 h after surgery. Postoperative nausea was reported in 2 patients of group Chlor-30 (14%) and 1 of group Chlor-40 (7%) (P = 0.21), and only 1 of the 2 patients of group Chlor-30 (7%) also vomited (P = 0.31).
No serious postoperative side effects or complications were recorded, and in no patient were signs of transient neurologic symptoms reported both at 24-h and 7-day phone follow-up.
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DISCUSSION |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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Recovery profiles reported in the present study with the three investigated doses are consistent with those reported in volunteer studies. Smith et al. (18) reported complete sensory regression within 98, 116, and 132 minutes after 30, 45, and 60 mg of 2-chloroprocaine, respectively; with times for recovery of ambulation ranging between 100 and 133 minutes; voiding occurred nearly 10 minutes later. Such recovery times are, in fact, shorter than those obtained with equivalent doses of lidocaine (17). In the same study, the authors reported that adding 0.2 mg epinephrine delayed the recovery profile of sensory and motor blocks by 50%. Most importantly, because 11 of the 18 volunteers receiving the epinephrine-containing solution reported nonspecific flu-like symptoms, the authors terminated the study and recommended that epinephrine should not be added to 2-chloroprocaine for spinal anesthesia.
In the present investigation, the 30-mg dose of 2-chloroprocaine was associated with a significant increase in the number of patients requiring fentanyl supplementation before the end of surgery and after an otherwise successful spinal block because of inadequate duration of surgical block as compared with the duration of surgery itself. This occurred more frequently with 30 mg (35%), less frequently with 40 mg (13%), and never with 50 mg (P = 0.014). This finding is related to the duration of surgery, which in the present study ranged between 30 and 60 minutes, rather than to efficacy of the anesthetic drug itself. Accordingly, the smallest dose of 2-chloroprocaine might be adequate for very short outpatient procedures taking <30 min; however, unless the physician is confident that the considered procedure will be completed within 20–30 minutes, the 30-mg dose should not be recommended (19). A useful option to implement adequacy of spinal block with 30 mg 2-chloroprocaine may be the addition of fentanyl or clonidine (24,25); however, additives have their own side effects, and the risk/benefit balance still needs to be clarified.
On the other hand, irrespective of the dose-duration relationships observed for several variables of spinal block profile, we did not observe earlier home discharge with the smaller doses. This was mainly related to the fact that in all patients voiding was required before discharge, and no differences in voiding time were reported among the three groups. Spontaneous voiding was the last criterion satisfied before fulfilling home discharge criteria in nearly all patients, and the lack of difference could be related to a type II error, as the study was only powered to detect differences in resolution of spinal block.
Voiding has been traditionally considered a prerequisite for home discharge after ambulatory surgery to avoid urinary retention; however, this can prolong hospital stay unnecessarily in up to 20% of patients. Interestingly, it has been reported that if no surgery-related or underlying risk factors for urinary retention are present, the incidence of urinary retention after discharging patients home without waiting for first micturition is acceptably low (26); and Mulroy et al. (27) suggested a relaxation of the requirements for voiding before home discharge in outpatients receiving spinal block with short-duration drugs and undergoing surgical procedures at low risk of urinary retention, such as lower limb surgery. This more aggressive approach to patient discharge after spinal anesthesia for lower limb surgery might potentially affect the interpretation of the present findings; however, further studies are required to better evaluate the safety of such an approach to home discharge criteria after spinal anesthesia.
The increasing percentage of surgical procedures performed on an outpatient basis, together with the reported incidence of transient neurologic symptoms after lidocaine spinal anesthesia, has renewed the interest in other short-acting local anesthetics, like 2-chloroprocaine. In the present study we did not report any case of neurologic complication using totally preservative and antioxidant-free 2-chloroprocaine. This finding is in agreement with findings reported in volunteer studies (17–19), which did not report any case of transient neurological symptoms after spinal chloroprocaine compared with 7 of 8 volunteers reporting transient neurological symptoms after lidocaine spinal block (17). The use of 2-chloroprocaine was first reported in more than 400 patients receiving intended spinal anesthesia and was considered a reliable and safe anesthetic for this use because of its potency, rapid onset, and rapid hydrolysis (8).
The present investigation was conducted before the Taniguchi et al. study (14) debated the concept that chloroprocaine-related neurologic toxicity reported in the 1980s after unintentional spinal injection during attempted epidural anesthesia was caused by the combination of low pH and the antioxidant sodium bisulfite (12,13). The mechanism of sulfite toxicity to the nervous cells is related to the alteration of the energetic metabolism in the cell mitochondria (28), and rats have a 10-fold larger expression of the sulfite oxydase enzyme than other species, including humans (16). The small sample size of the present investigation prevents us from drawing any conclusion about the safety profile of this drug for spinal injection, and additional data are needed to clarify this aspect; however, studies in volunteers and reports on off-label use of spinal 2-chloroprocaine in clinical practice support the safety profile of the preservative-free formulation of this drug for intrathecal injection (17–21).
In conclusion, 40 to 50 mg of plain chloroprocaine 1% provided adequate spinal anesthesia for lower limb outpatient procedures lasting 45 to 60 min. Reducing the dose of 2-chloroprocaine to 30 mg resulted in a spinal block of insufficient duration and had no advantages in terms of home discharge time.
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Footnotes |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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This article has been cited by other articles:
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  S. L. Shafer Anesthesia & Analgesia's Policy on Off-Label Drug Administration in Clinical Trials Anesth. Analg., July 1, 2007; 105(1): 13 - 15. [Full Text] [PDF]
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A. Casati, G. Fanelli, G. Danelli, M. Berti, D. Ghisi, M. Brivio, M. Putzu, and A. Barbagallo Spinal Anesthesia with Lidocaine or Preservative-Free 2-Chlorprocaine for Outpatient Knee Arthroscopy: A Prospective, Randomized, Double-Blind Comparison Anesth. Analg., April 1, 2007; 104(4): 959 - 964. [Abstract] [Full Text] [PDF]
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