As the shift toward ambulatory surgery continues, the interest in available drugs for outpatient spinal anesthesia also increases. An ideal anesthetic for spinal anesthesia in ambulatory surgery patients would provide rapid onset of action, adequate potency, predictable duration, and decreased neurotoxicity and systemic side effects. Procaine is unreliable, with a failure rate of 17%, and is perhaps useful for only the shortest procedures (1). Lidocaine can be associated with symptoms of transient neurologic syndrome (TNS) (2). Bupivacaine can result in unpredictable duration of block, even with smaller doses, and can lead to delays in discharge.
In 1952, Foldes and McNall (3) showed that spinal anesthesia performed with preservative-free 2-chloroprocaine (2-CP) produced blocks with rapid onset, increased potency in comparison with procaine, and no evidence of toxicity in 214 patients. In the early 1980s, there were three reports describing neurologic deficits in eight patients (five of them obstetric) after the accidental intrathecal injection of large volumes of a bisulfite-containing formulation of 2-CP (known as Nesacaine-CE) intended for the epidural space (4). Lower extremity paralysis and sacral neurological dysfunction were noted, with partial to complete resolution achieved by 6–12 wk in most, though persisting permanently in some. After extensive investigation, it was discovered that a combination of low pH and sodium bisulfite (an antioxidant) in the anesthetic preparations was the culprit in the incidence of neurologic injury (5,6). 2-CP is once again available in a preservative-free and antioxidant-free form (Nesacaine-MPF, Astra Pharmaceuticals, Worchester, MA; generic chloroprocaine, Bedford Laboratories, Bedford, OH), and this has rekindled interest in its use for outpatient spinal anesthesia.
The addition of intrathecal opioids to spinal anesthesia prolongs sensory blockade without prolonging motor recovery (7–9). Liu et al. (7) studied 8 volunteers receiving intrathecal 5% lidocaine with and without fentanyl, showing that fentanyl lengthened the duration of tolerance to tourniquet pain without delaying motor blockade or time to void. Chilvers et al. (8) showed that 25 μg of intrathecal fentanyl provided improved intraoperative and postoperative analgesia in small dose lidocaine spinal anesthesia. Ben-David et al. (9) performed spinal anesthesia in 50 arthroscopic patients with bupivacaine with or without fentanyl with similar findings. Intravenous opioids enhance the spread of spinal anesthetics (10–13). In an effort to compare the efficacy of intrathecal versus IV opioids, Siddik-Sayyid et al. (13) studied 48 healthy parturients having elective cesarean deliveries. Study participants received spinal bupivacaine either with 12.5 μg fentanyl intrathecally or IV and demonstrated a lower visual analog scale score intraoperatively, and a delay in request for supplemental analgesia in those with the intrathecal opioid. Therefore, the primary objective of our investigation was to explore the effect of adding intrathecal fentanyl on the quality, duration, and recovery from 2-CP spinal anesthesia using a volunteer model.
After IRB approval and written informed consent specifying that the use of both preservative free 2-CP and the use of fentanyl for spinal anesthesia are off-label applications, eight healthy volunteers were enrolled in this double-blinded, randomized study. Each volunteer received 2 spinal anesthetics, separated by at least 48 h, one with 2 mL plain preservative-free 2% 2-CP (40 mg) and 0.4 mL saline, and the other containing 2 mL preservative-free 2% 2-CP (40 mg) and 0.4 mL fentanyl (20 μg). The fentanyl dose was chosen based on previous lidocaine spinal anesthetic studies (5,8). A random number generator was used to determine the order of drug administration, and all solutions were prepared by the Virginia Mason investigational pharmacy. All subjects had fasted for 6 h and received no sedatives during the study. Before subarachnoid block, a 20-gauge peripheral IV line was placed and an IV bolus of lactated Ringer’s solution (6 mL/kg) was administered, followed by an infusion of 8 mL · kg−1h−1 for the first hour and 2 mL · kg−1h−1 thereafter. Vasoactive drugs were administered only if symptoms of hypotension or bradycardia developed.
Spinal anesthesia was administered with the volunteers in the left lateral decubitus position. Under sterile conditions and after local infiltration of the skin with 1% lidocaine, the subarachnoid space was entered at the L2-3 interspace via the midline approach using a 20-gauge introducer and a 24-gauge Sprotte needle. With the spinal needle orifice facing cephalad, 0.2 mL of the cerebrospinal fluid was aspirated, followed by injection of the study solution at a rate of 0.25 mL/s. After drug administration, a second 0.2-mL aspiration and reinjection of cerebrospinal fluid was used to confirm intrathecal injection. Subjects were immediately laid supine for the remainder 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 at 10-min intervals 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 six common surgical sites: at the lateral ankle (S1) bilaterally, at the medial knee (L3) bilaterally, at the pubis midline (T12), and at the umbilicus midline (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 mA and then with increasing increments of 10 mA to a maximum of 60 mA. This maximum limit was chosen because previous studies have shown TES at 60 mA to be equivalent to the intensity of stimulation caused by surgical incision (14). Testing began in a systematic cephalad-to-caudad order at 4 min after injection and continued at 10-min intervals until the subject could no longer tolerate 60 mA on 2 successive tests. If the subject was never able to tolerate 60 mA, the testing was terminated at 34 min.
Thirty minutes after injection, duration of the tolerance to left thigh tourniquet was assessed using a 34-in. pneumatic cuff that was inflated to 300 mm Hg after exsanguination by gravity. This is similar to the tourniquet application used in lower extremity orthopedic procedures at our institution. The subjects were instructed to request deflation of the tourniquet when the discomfort level reached a pain score of 5 on a 10-point scale or at a maximum time limit of 120 min.
Motor block of the abdominal and lower extremity muscles was assessed using electromyography (EMG), isometric force dynamometry, and modified Bromage scale as used in previous lidocaine studies (5). To test abdominal muscle strength, an EMG lead was placed over the body of the rectus abdominus muscle to the left of the umbilicus. A restraining strap was placed across the body at the level of the xiphoid, and an isometric maximal contraction of abdominal muscle flexion against the strap was conducted. Using a commercially available surface EMG (MyoTrac2; Thought Technology Ltd., Montreal, PQ), an averaged, rectified measurement 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 right gastrocnemius (plantar flexion against resistance). 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 (no block = 0, able to bend the knee = 1, able to dorsiflex the foot = 2, and complete motor block = 3) were recorded every 10 min after injection until the resolution of the motor block or until 40 min if no motor block was achieved.
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, they then attempted to void. Bladder volumes were assessed using bladder ultrasounds pre- and postvoid. If either ambulation or voiding were unsuccessful, then the attempts were repeated at 10-min intervals until these end-points were achieved. Volunteers were questioned daily for 72 h regarding the presence of headache, backache, or other symptoms.
For statistical analysis, each dermatome above S3 was assigned an integer (i.e., S2 = “1,” T10 = “10,” and T1 = “19”), and all dermatome levels blocked to pinprick were averaged for each dose to determine the estimated time course of sensory anesthesia to pinprick. Peak block height comparisons were made using Mann-Whitney U-test. Comparisons of dermatome regression over time, isometric force dynamometry, and hemodynamic data were made using repeated-measures analysis of variance (ANOVA). Paired Student’s t-tests were used to determine differences between anesthetics for all other measurements. Unless otherwise specified, data are mean ± sd, with significance defined as P < 0.05.
Spinal anesthesia was successfully performed for all subjects. There were 3 males and 5 females aged 37 ± 13 yr, weighing 71 ± 16 kg, and 169 ± 9 cm in height. Participants received 681 ± 193 mL of crystalloid. Complete regression of block, with ability to ambulate and void was achieved for all volunteers by 110 min.
Key sensory characteristics of the spinal anesthetic blocks are summarized in Table 1. Notably, the peak block height was higher in the fentanyl group although the time to achievement of peak block did not differ between the two groups. The addition of intrathecal fentanyl resulted in significantly longer sensory blockade, as demonstrated in the time to L1 regression and complete sensory regression. When comparing dermatomes, this lengthening of sensory blockade was reduced as the block regressed (Fig. 1). Tourniquet was tolerated longer in the fentanyl group (51 ± 8 min versus 34 ± 14 min, P = 0.02) (Fig. 2). Although there seemed to be a trend toward lengthening of tolerance to TES in the fentanyl group, not all dermatomes were significantly different.
The duration of sensory blockade was extended with intrathecal fentanyl and motor blockade was minimally affected. Although motor block as assessed by the Bromage scale was of longer duration, when measured by abdominal EMG and lower extremity isometric force dynamometry, the onset and duration of motor block were unaffected by the addition of intrathecal fentanyl (Table 1, Fig. 3). All subjects were able to ambulate and void successfully after full return of sensation to pinprick to the S2 dermatome in both groups, and all were deemed appropriate for discharge once these goals were achieved. The intrathecal fentanyl group experienced only a minor delay in discharge (104 ± 7 versus 95 ± 9 min). There was no difference in pre- and postvoid bladder volumes between the groups.
There were no serious complications in the eight study volunteers, including no cases of bradycardia or hypotension, and no subject required vasoactive medications. There was a significant decrease in heart rate and systolic blood pressure compared with baseline (P < 0.01 for both), but there were no differences between the two groups (P > 0.05). All participants in the fentanyl group experienced pruritus, ranging from mild to moderate in severity. For seven of these volunteers, the pruritus regressed segmentally and completely disappeared with resolution of the spinal chloroprocaine block (Table 2). The other volunteer continued to have itching of the legs for 1 h after ambulation. No participant required treatment for pruritus and no pruritus was experienced in the saline group. Follow-up after 72 h revealed no cases of spinal headache or nausea and no complaints of backache or other symptoms consistent with TNS.
The primary finding of this study is that the addition of 20 μg of intrathecal fentanyl to 2-CP spinal anesthesia prolongs sensory blockade but only minimally lengthens motor blockade. Regression of block to L1 was lengthened by 25 min and tolerance to tourniquet was extended by 17 min on average. Both thoracic and lumbar dermatomes experienced significantly longer sensory blockade (Fig. 1). Although this eventually translated to a slight delay in discharge, the difference narrowed to an average of only a 9-min delay for the fentanyl group, and all subjects were able to ambulate within 110 min after injection.
Several measurements were used to evaluate the return of motor function. The Bromage scoring system demonstrated a longer time to recovery of lower extremity movement in the fentanyl group. However, the time to return to normal lower extremity movement (Bromage) for both groups was shorter than the times to return to full quadriceps and gastrocnemius muscle strength, confirming that Bromage scoring is less sensitive than isometric force dynamometry in assessing return to full motor function.
Our results are consistent with prior findings showing improvement of local anesthetic effect for use in spinal anesthetics with the addition of intrathecal opioids (7,9). Animal models have similarly shown a synergistic relationship between opioids and local anesthetics in analgesia, allowing for adequate analgesia without motor blockade using subtherapeutic doses of local anesthetic (15). Although intrathecal local anesthetics are nonselective in their blockade of afferent and efferent pathways, the addition of opioids has an effect on the afferent nociceptive fibers without an effect on sympathetic efferent fibers (16). Fentanyl was able to depress C-fiber reflexes alone, whereas the opioid-local anesthetic combination resulted in depression of both A δ and C reflexes without efferent effect.
The use of 2-CP in combination with opioids for epidural blockade has been called into question. Grice et al. (17) studied the interactions between 2-CP and bupivacaine/fentanyl epidurals for labor analgesia and found that prior test dose injection of 2-CP decreases the duration of analgesia achieved with a subsequent bupivacaine/fentanyl epidural injection. Another study suggested that epidural morphine is antagonized by 2-CP, resulting in increased IV patient-controlled analgesia morphine use postoperatively in obstetric patients (18). Similar results have been found in the antagonism of epidural clonidine with 2-CP (19). The mechanism is unknown, but it has been proposed to be secondary to a mu receptor specific etiology (20). Conversely, in our study, the combination of 2-CP and fentanyl was found to be instead synergistic. It is possible that the interaction of the two drugs is exhibited differently in the intrathecal space.
Pruritus was the only side effect noted by our study participants in the fentanyl group. Under usual surgical circumstances patients would have received sedation that may have diminished this side effect. With judicious use of antipruritic therapy, the itching would also likely have been minimized. Pruritus has been noted in other studies combining fentanyl with local anesthetics for spinal anesthesia (7,9), and our results are consistent with these findings. As with other characteristic side effects of opioids, this is likely dose dependent and may warrant further studies.
Our subjects did not experience any measured nausea or urinary retention. No respiratory depression was detected, but our standard monitors were not likely sensitive enough to detect a subtle change. It has been observed in previous studies that the intrathecal fentanyl dose associated with respiratory depression in the elderly is 50 μg, whereas 25 μg was tolerated without respiratory events (21). In a separate study comparing doses of intrathecal fentanyl at 0, 5, 10, 20, 40, and 50 μg, no respiratory depression, hypoxemia, or hemodynamic changes were noted in elderly patients receiving lower extremity revascularization procedures (22). Interestingly, pruritus was noted with increasing opioid doses in this study.
There were no complaints of neurotoxicity or TNS in the 72-h follow-ups. The use of 2-CP in the intrathecal space and the possibility of neurotoxicity has been controversial. It is understandable that physicians would be reluctant to reintroduce 2-CP into common use for spinal anesthetics when it has been previously implicated in reports of morbidity. In the eloquent article previously referenced by Winnie and Nader (4), the history of 2-CP and the elucidation of the cause for neurotoxicity were reviewed, offering compelling evidence that 2-CP in an antioxidant-free environment is safe. Furthermore, a Food and Drug Administration meeting held to specifically address this issue eliminated chloroprocaine as a cause (5). To the cautious practitioner, it should be noted that 2-CP is still available in generic form that contains sodium metabisulfite at a pH of 3.1 (generic chloroprocaine; Abbott Laboratories, North Chicago, IL). Although our study was small, it continues to validate our hypothesis that 2-CP is safe.
In conclusion, we found that 2-CP has fast onset, predictable duration, and adequate potency for use in spinal anesthesia. Although there were no reported symptoms of TNS, as the number of subjects in this initial study is quite small, large-scale clinical trials will be necessary to further delineate the safety of spinal 2-CP. The addition of intrathecal fentanyl significantly prolonged sensory blockade while only minimally extending the time to ambulation, void, and discharge. This makes the combination of 2-CP (40 mg) and fentanyl (20 μg) an attractive choice for spinal anesthesia in the outpatient setting.
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