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Departments of *Anesthesiology and Intensive Care and
Surgery, University Hospital, Örebro, Sweden
Address correspondence to I. Dobrydnjov, Department of Anesthesiology and Intensive Care, University Hospital, SE 701 85 Örebro, Sweden. Address e-mail to igor.dobrydnjov{at}orebroll.se
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Abstract |
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IMPLICATIONS: The addition of clonidine 15 µg to 6 mg of hyperbaric bupivacaine increases the spread of analgesia, prolongs the time to first analgesic request, and decreases postoperative pain, compared with bupivacaine alone, during inguinal herniorrhaphy under spinal anesthesia.
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Introduction |
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The 
2-adrenergic agonist clonidine has a variety of different actions, including the ability to potentiate the effects of local anesthetics (8–10). However, unlike spinal opioids, clonidine does not produce pruritus or respiratory depression. It also prolongs the sensory blockade (9,11) and reduces the amount or concentration of local anesthetic required to produce postoperative analgesia (12,13). However, intrathecal clonidine at the usual dose (1 to 2 µg/kg) is associated with bradycardia, relative hypotension, and sedation. The aim of this randomized double-blinded study was to investigate the efficacy and adverse effects of small doses of intrathecal clonidine added to small-dose hyperbaric bupivacaine for inguinal herniorrhaphy.
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Methods |
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Patients were randomly allocated to one of three treatment groups, each comprising 15 patients, by using computer-generated random numbers inserted into sealed envelopes marked 1–45. The study solutions were prepared in a separate area by a person not involved in the patients’ care, and the patients and anesthesiologist were blinded to the study solutions.
The following drug combinations were slowly injected intrathecally over 3 min. Patients in Group B received 6 mg of bupivacaine in 8% glucose (0.5% Marcain Spinal Heavy; Astra, Sodertalje, Sweden); patients in Group BC15 received 6 mg of bupivacaine in 8% glucose and 15 µg of clonidine (0.015% Catapressan; Boehringer Ingelheim KG, Germany); and patients in Group BC30 received 6 mg of bupivacaine in 8% glucose and 30 µg of clonidine. All test solutions were diluted with saline to a total volume of 3 mL.
All patients received midazolam 1–2 mg IV as premedication and paracetamol 1 g rectally. Lactated Ringer’s solution (250 mL) was administered before surgery followed by an infusion of 250 mL during the operation. Heart rate (HR) and noninvasive mean arterial blood pressure (MAP) were measured at 5- to 15-min intervals during induction, surgery, and recovery by using Datex-Engstrom AS/3. Clinically relevant bradycardia was defined as a decrease in HR of <50 bpm and was treated with atropine 0.5 mg IV. Clinically relevant hypotension constituted a decrease of 20% or more in systolic blood pressure from baseline values and was treated with ephedrine 5 mg IV. Arterial oxygen saturation was registered continuously by pulse oximetry.
Patients were placed in the horizontal lateral position, with the operative site down. A midline lumbar puncture was performed at the L2-3 interspace by using a 27-gauge Whitacre spinal needle with the bevel of the needle directed to the dependent operative side. All patients remained in the lateral position for 15 min and were then placed in a horizontal supine position for the operation. The time at which the intrathecal injection was completed was considered as zero (t = 0).
If the patient preferred sedatives, midazolam IV was given intermittently in 1-mg doses during the operation. If the patient expressed a need for additional analgesia because of intraoperative pain, IV fentanyl 50 µg was given. If the block was inadequate or the patient complained of pain not relieved by two doses of fentanyl, a general anesthetic was administered by using propofol for induction and sevoflurane in oxygen and nitrous oxide for maintenance with a laryngeal mask. No additional local anesthetic was injected in any patient before or during the operation.
The level and duration of sensory block—defined as the loss of sharp sensation with the pinprick test—were recorded bilaterally. Data were registered at 5-min intervals for the first 15 min, at 15-min intervals for 15–150 min, and then every 30 min. During the regression phase, time to two-segment regression and time to full skin sensibility at the S1 segment were registered. Motor block was measured bilaterally by using a modified Bromage scale (0–3) with the same time intervals. When the patients had a Bromage grade of 0 and full skin sensibility at the S1 segment and were alert, they were asked to stand and walk. The times to standing and to walking were recorded.
After surgery, pain intensity at rest and on movement (raised head and attempt to sit up) was assessed with a 10-cm visual analog scale (VAS; 0 = no pain and 10 = worst imaginable pain). Postoperative pain was treated by using paracetamol 1 g orally every 6 h in all patients. Dextropropoxyphene 100 mg orally was given when requested by the patient for mild to moderate pain (VAS <5). For severe pain (VAS 
5), ketobemidone (a synthetic opioid, equipotent with morphine) was given IV in 1-mg incremental doses. The time to request for the first dose of analgesic and the total dose of analgesics were recorded. Sedation was assessed with a four-point verbal rating scale (1 = no sedation, 2 = light sedation, 3 = somnolence, 4 = deep sedation).
Elapsed time between intrathecal injection and spontaneous urination was recorded. Ultrasound-guided scanning of the urinary bladder was performed with the Bladder Scan® 4 h after the spinal anesthetic to evaluate urinary retention. Patients with a residual volume >500 mL were catheterized. Adverse effects such as pruritus, postoperative nausea and vomiting (PONV), headache, and low back pain were recorded. When their vital signs were stable for at least 1 h and the patients were oriented; could tolerate oral intake, urinate, and walk; and had adequate pain control, they were discharged with an escort.
During surgery, the surgeon assessed the quality of anesthesia by using the following four-point scale: 4, excellent; 3, good; 2, inadequate; and 1, poor. After surgery, the patients were interviewed regarding their opinion of the anesthetic procedure according to the same scale. A follow-up was done daily for 1 wk by using a questionnaire to assess pain and recovery.
Unless otherwise stated, results are expressed as means ± SD or median (range). All normally distributed continuous variables were analyzed by one-way analysis of variance with the factor treatment. Group means (VAS, MAP, and HR) were tested by using Tukey’s test. The block heights and the number of dermatomes blocked in the three groups were assessed with the Kruskal-Wallis test. If there were significant differences, the analysis was continued with post hoc comparisons of differences between pairs of groups by using the Mann-Whitney U-test. Differences in nominal categorical data between the study groups were tested by the 
2 test. A P value <0.05 was considered statistically significant.
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Results |
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The sensory block assessments are summarized in Figure 1 and Table 1. The cephalad spread of sensory block on the dependent side was significantly higher (two to four dermatomes) in Groups BC15 (P < 0.05) and BC30 (P < 0.02) compared with Group B. The level of analgesia was insufficient for surgery in 5 patients (33%) in Group B, compared with none in Groups BC15 and BC30, and these patients were given a general anesthetic (P < 0.05). Seven patients in Group B (47%), 3 in Group BC15 (20%), and 2 in Group BC30 (13%) had complete unilateral sensory block as measured by pinprick. The median upper level of sensory block on the nondependent side was T10 in Group B versus T8 in Group BC15 and T6 in Group BC30 (P < 0.05). The time to two-segment regression of sensory block on the dependent side was significantly shorter in Group B compared with Group BC30 (P < 0.05). Duration of anesthesia, estimated as the time to full skin sensibility at the S1 segment, was significantly longer in Group BC30 than in Groups B and BC15 (P < 0.05). However, there were no differences between Groups B and BC15.
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No differences were found among the groups in any of the variables of recovery (Table 1). The bladder was catheterized in three patients with an enlarged prostate (one in Group B and two in Group BC15) because of a residual urine volume of more than 500 mL.
Postoperative pain relief at rest was satisfactory in all patients (mean VAS approximately 2–3) irrespective of group (Fig. 2). VAS at rest and on movement was significantly lower in Groups BC15 and BC30 compared with Group B during the first 210 min. All 15 patients in Group B needed supplementary analgesics (ketobemidone, dextropropoxyphene, or both) in the postanesthesia care unit (PACU) (Table 2), compared with 11 patients in Group BC15 (not significant) and 10 patients in Group BC30 (P < 0.05). The mean time to first request for analgesics was significantly shorter for Group B than for Group BC15 (P < 0.02) and Group BC30 (P < 0.05). The mean dose of dextropropoxyphene was smaller in patients who received clonidine (P < 0.02). The mean dose of ketobemidone was also smaller in Groups BC15 and BC30 than in Group B, although this did not reach statistical significance.
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Four patients, one in Group BC15 and three in Group BC30, had mild orthostatic hypotension during the initial attempts at mobilization. However, there were no significant differences in MAP or HR among the groups on standing and on walking.
Four patients complained of PONV (one patient each in Groups B and BC30 and two patients in Group BC15), and one patient had pruritus in Group BC15. One patient in Group B experienced dizziness. Two patients had headache (one each in Groups B and BC30), but neither of these was a typical postdural puncture headache. Two patients in Group B complained of back pain. No significant difference in sedation was found among the groups. No case of respiratory depression was observed during the investigation.
The surgeon rated the operating conditions as excellent or good in 93%–100% of patients in Groups BC15 and BC30 and in 53% of those in Group B (P < 0.05). When interviewed before discharge, 100% of patients in Groups BC15 and BC30 rated the anesthesia method as excellent or good, compared with 40% of those in Group B (P < 0.05). The other patients rated the anesthesia method as satisfactory or inadequate. There were no significant differences in adverse effects (PONV, pruritus, headache, or low back pain) among the groups on Days 1–3 after surgery.
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Discussion |
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Intrathecal clonidine clearly increases the duration of both sensory and motor block (8–10,16), as well as postoperative pain relief (12). De Kock et al. (17) recommended a dose of 15–45 µg of clonidine as optimal for supplementing spinal anesthesia. In our study, 15 and 30 µg of clonidine were compared. Analgesia was significantly increased in our study by 15 µg of intrathecal clonidine. Importantly, increasing the dose of clonidine from 15 to 30 µg did not increase the duration of analgesia. Although clonidine in doses of 30 µg did not prolong the time until walking and voiding, recovery of sensory and motor block was delayed significantly.
The mechanism of clonidine-induced potentiation of sensory block in spinal anesthesia is reported to be mediated by presynaptic (inhibition of transmitter release) (18) and postsynaptic (enhancing hyperpolarization) (19,20) effects. Although clonidine might have a vasoconstrictive effect in large concentrations, the role of vasoconstriction in prolonging sensory block seems to be minor, even in usual clinical doses (1–2 µg/kg) (9,21). Intrathecal clonidine alone, even in doses of up to 450 µg, does not induce motor block or weakness (22). In contrast, intrathecal clonidine combined with local anesthetic significantly potentiates the intensity and duration of motor blockade (8–10). The explanation for this could be that the 2-adrenoceptor agonists induce cellular modification in the ventral horn of the spinal cord (motoneuron hyperpolarization) and facilitate the local anesthetic action. However, these effects seem to be dose related, because 30 µg, but not 15 µg, of clonidine added to bupivacaine potentiated motor block. Similar effects were also observed on the nondependent side.
A small dose of intrathecal clonidine is not usually associated with systemic side effects such as bradycardia, hypotension, or sedation (17). Although the mean systolic and diastolic blood pressures decreased during spinal anesthesia, in our study this effect was of minor clinical importance. During the first 45–120 minutes after the intrathecal injection, a decrease in MAP was observed in those patients who received clonidine, but only one patient in Group BC30 had hypotension requiring ephedrine. The absence of severe hypotension could be explained by the unilateral spinal anesthesia, which is associated with fewer blocked segments so that the extent of sympathetic block is less (23). Also, a smaller dose of anesthetic allows for activation of homeostatic vasoconstrictive compensatory mechanisms.
The mean time to first urination was longer than the mean time to complete resolution of the motor and sensory block. This is in accordance with other studies, in which patients were able to walk before they could urinate (24,25). Another explanation for the prolonged time until voiding in our patients could be the small volume of urine in the bladder. Because the patients did not receive any oral fluids for at least eight hours before surgery and because the total volume of IV fluids was only 500 mL (6–6.5 mL/kg), there was minimal risk of bladder distension or volume overloading. This was confirmed by the fact that the mean volume of urine four hours after spinal injection in patients who did not void was 206 mL. Moreover, except for the three patients with known prostate adenoma, all our patients were advised not to attempt to pass urine before they had a natural urge to do so.
In conclusion, this study has shown that use of clonidine as adjuvant to small-dose (6 mg) bupivacaine is effective for ambulatory inguinal herniorrhaphy. The addition of intrathecal clonidine 15 or 30 µg to small-dose bupivacaine increased the spread and duration of analgesia and produced an effective spinal anesthesia. Clonidine 15 µg combined with bupivacaine 6 mg in 8% glucose did not produce prolonged postoperative motor block and is therefore to be preferred for inguinal herniorrhaphy.
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Acknowledgments |
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The authors thank the following people for their help in various stages of the study: Annette Dahlqvist, Chris Hedenskog, and Pia Skoog for meticulously maintaining patient records; Eva Johanzon for data extraction and transfer; and personnel in the operating theaters and Day Surgical Unit for their constant support.
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This article has been cited by other articles:
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  B. R. Davis and D. J. Kopacz Spinal 2-Chloroprocaine: The Effect of Added Clonidine Anesth. Analg., February 1, 2005; 100(2): 559 - 565. [Abstract] [Full Text] [PDF]
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J. R. Yoos and D. J. Kopacz Spinal 2-Chloroprocaine: A Comparison with Small-Dose Bupivacaine in Volunteers Anesth. Analg., February 1, 2005; 100(2): 566 - 572. [Abstract] [Full Text] [PDF]
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A. Casati, E. Moizo, C. Marchetti, and F. Vinciguerra A Prospective, Randomized, Double-Blind Comparison of Unilateral Spinal Anesthesia with Hyperbaric Bupivacaine, Ropivacaine, or Levobupivacaine for Inguinal Herniorrhaphy Anesth. Analg., November 1, 2004; 99(5): 1387 - 1392. [Abstract] [Full Text] [PDF]
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S. Strebel, J. A. Gurzeler, M. C. Schneider, A. Aeschbach, and C. H. Kindler Small-Dose Intrathecal Clonidine and Isobaric Bupivacaine for Orthopedic Surgery: A Dose-Response Study Anesth. Analg., October 1, 2004; 99(4): 1231 - 1238. [Abstract] [Full Text] [PDF]
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