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Anesth Analg 2005;100:873-878 © 2005 International Anesthesia Research Society doi: 10.1213/01.ANE.0000143950.13939.7A
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Abstract |
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We evaluated the systemic and local effects of clonidine as an analgesic adjunct to psoas compartment block (PCB) with levobupivacaine. In a randomized, prospective, double-blind trial, 36 patients requiring hip fracture surgery received PCB and general anesthesia. Patients were randomized into three groups. Each patient received PCB with 0.4 mL/kg of levobupivacaine 0.5%. The control group (group L) received IV saline, the systemic clonidine group (group IC) received IV clonidine 1 µg/kg, and the peripheral clonidine group (group C) received IV saline and PCB with clonidine 1 µg/kg. The interval from time of completion of block injection to first supplementary analgesic administration was longer in group IC compared with group L (mean ± sd, 13.4 ± 6.1 versus 7.3 ± 3.6 h; P = 0.03). There was no difference between group C and group L (10.3 ± 5.9 versus 7.3 ± 3.6 h; P > 0.05). The groups were similar in terms of 24 h cumulative morphine and acetaminophen consumption. There were no significant differences among groups regarding postoperative adverse effects (bradycardia, hypotension, sedation, and nausea). We conclude that IV but not perineural clonidine (1 µg/kg) prolongs analgesia after PCB without increasing the incidence of adverse effects.
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Introduction |
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Single-shot psoas compartment block (PCB) provides effective analgesia after hip surgery but is limited to 6 h duration (1). Continuous catheter techniques facilitate prolonged postoperative analgesia (2) but require greater technical skill, additional time and equipment to initially place, and postoperative monitoring (3).
Analgesic adjuncts such as the 
2 adrenoceptor agonist, clonidine, have been combined with local anesthetics (LA) to prolong the duration of peripheral nerve blocks (4). The addition of 150 µg clonidine to mepivacaine prolongs anesthesia and analgesia after single-shot brachial plexus block (5). Perineural clonidine also prolongs duration of analgesia of brachial plexus block with bupivacaine 0.25% (6).
The location of 2A receptors in the locus ceruleus of the brainstem and 2B receptors in the thalamus indicate possible supraspinal sites for the analgesic action of clonidine (7). An equivalent dose of clonidine (2 µg/kg), administered IV and caudally, provided similar duration of postoperative analgesia (8). A systemic clonidine control group is required to investigate whether an analgesic effect of perineural clonidine is mediated centrally or via enhancement of LA action.
Levobupivacaine is increasingly replacing bupivacaine in regional anesthesia as a result of its similar potency, but longer duration of action and safer cardiotoxic profile (9). The effect of clonidine on single-shot levobupivacaine 0.5% has not been investigated in any clinical setting.
The aims of our study were to determine if clonidine, as an adjunct to levobupivacaine 0.5% in PCB, prolongs the duration of analgesia after hip surgery and to compare the analgesic effect of clonidine when administered IV as compared with clonidine coadministered with levobupivacaine for the PCB.
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Methods |
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After institutional ethical committee approval and having obtained written informed consent, 36 patients scheduled for surgical repair (dynamic hip screw fixation or hemi-arthroplasty) of traumatic hip fractures were enrolled in a prospective, double-blind, randomized, controlled trial. Exclusion criteria were concurrent medication with adrenoceptor agonists or antagonists or contraindications to regional anesthesia. All patients underwent PCB followed by general anesthesia.
Patients were randomly assigned to 1 of 3 groups according to a randomization table restricted to blocks of 12. The results were made available to the investigators using sealed envelopes, one for each patient recruited. Patients in group L received 0.4 mL/kg of levobupivacaine 0.5% (Chirocaine®, Abbott Laboratories, Dublin, Ireland) for PCB and 0.9% saline 5 mL IV. Patients in group C received 0.4 mL/kg of levobupivacaine 0.5% in combination with 1 µg/kg clonidine (Catapres®, Boehringer Ingelheim, Berkshire, England) for PCB and 0.9% saline 5 mL IV. Patients in group IC received 0.4 mL/kg of levobupivacaine 0.5% for PCB and clonidine 1 µg/kg IV made up to 5 mL with 0.9% saline. The drug solutions to be administered were prepared by an anesthesiologist not involved in block performance, patient care, or data collection.
Patients arrived in the anesthesia induction room receiving maintenance IV fluids. Routine monitoring consisted of continuous electrocardiography, pulse oximetry, and noninvasive blood pressure at 5-min intervals until the end of surgery. (AS 3, Datex, Instrumenterium Corp. Finland). Before positioning for PCB, patients received 1–2 µg/kg fentanyl IV. Baseline arterial blood pressure was recorded and 8 mL/kg Hartmann’s solution was rapidly administered.
The patients were placed in the lateral position, operative side uppermost. The technique for PCB was that as described by Capdevila et al. (2). The same operator (SM) performed all the blocks. After skin preparation, 3 mL 1% lidocaine was injected at the site of insertion. A Stimuplex A® 100-mm needle (B Braun Medical, Melsungen, Germany) was inserted perpendicular to all planes using a nerve stimulator (Stimuplex HNS 11®, B Braun Medical) with a starting output of 1.5 mA and 2 Hz. The needle was advanced until quadriceps twitches were elicited or bony contact (presumed to be the transverse process of fourth lumbar vertebra) was made. If the needle encountered bone, it was withdrawn to skin and redirected caudad under the transverse process and advanced until quadriceps twitches were elicited with a current between 0.3 and 0.5 mA. After negative aspiration for blood, the LA solution was injected over approximately 3 min in 5-mL increments. The time at which all LA had been injected was taken as time zero. The patients were returned to the supine position and the IV solution administered over 5 min.
The following were recorded at 5, 15, 30, and 45 min after completion of LA injection: heart rate, arterial blood pressure, sensory block, and motor block. Sensory block of the femoral nerve (anterior thigh), lateral femoral cutaneous (LFC) nerve (lateral thigh), and S1 root (sole of foot) were evaluated using ethyl chloride spray and compared with the contralateral leg. Sensation was scored as follows: 0 = no difference, 1= less cold, 2 = not cold. Blockade of the obturator nerve was evaluated by degree of motor block. Patients were asked to adduct their thigh and were scored as follows: 0 = normal power, 1 = weakness in adduction, 2 = paralysis of adduction. Onset of sensory and motor block was defined as time to complete thermoanesthesia and adductor paralysis, respectively. Inadvertent epidural spread was determined using ethyl chloride spray bilaterally from T4 to S1 dermatomes and recorded as present or absent.
Patients were scheduled for surgery 45 min after the block. Patients showing no evidence of peripheral nerve blockade at this time received an alternative anesthetic technique and were excluded from the study.
Patients were anesthetized using an inhaled gas induction with 2%–4% sevoflurane end-tidal concentration (ET%) in 50:50 oxygen/nitrous oxide at a fresh gas flow rate of 8 L/min. After loss of eyelash reflex, a laryngeal mask was inserted. Anesthesia was maintained with sevoflurane 0.5%–2.0% ET% in 50:50 oxygen/nitrous oxide at a fresh gas flow of 2 L/min with spontaneous respiration. Fentanyl 1µg/kg was administered if intraoperative systolic blood pressure increased more than 30% from baseline or heart rate exceeded 100 bpm despite 2 increases in sevoflurane ET% by 0.5%. Maintenance and replacement fluids consisted of Hartmann’s solution and were administered at the discretion of the attending anesthesiologist with blood loss replaced mL for mL with the same solution. Hypotension was defined as a decrease in systolic blood pressure more than 30% from baseline. Hypotension was treated with increments of ephedrine IV (6 mg each). Bradycardia was defined as a heart rate <60 bpm.
Postoperatively the following data were recorded at 3, 6, 12, 16, and 24 h after performance of the PCB, by investigators blinded to group assignment: heart rate, arterial blood pressure, nausea/vomiting, sedation score, pain scores at rest and on movement, femoral and LFC sensory block, and obturator motor block. Patients were cared for in the recovery room until suitable for discharge to the ward.
Sedation was scored as 0 = awake, 1 = drowsy, 2 = asleep but rousable, 3 = comatose. No sedatives were administered in the 24 h after block insertion. Nausea and/or vomiting were recorded as present or absent. Antiemetic administration (IM cyclizine 50 mg every 8 h if required) in the 24-h period was recorded.
Pain was assessed by the investigators at each time point using a standard verbal rating score (VRS) for all patients with 0 = "no pain" and 10 = "worst pain you could imagine." Pain was assessed at rest and on passive flexion of the operated hip to 30 degrees.
When patients first complained of pain on the ward, nursing staff assessed pain using our institution’s pain scale as follows: 0 = no pain, 1 = mild pain, 2 = moderate pain, 3 = severe pain, and 4 = unbearable pain. Oral or rectal acetaminophen 1 g was administered if patients complained of mild postoperative pain or IM morphine 0.1 mg/kg if patients complained of moderate or severe pain. Acetaminophen was administered at 6 hourly and morphine at 4 hourly intervals as required for pain. Pain persisting immediately after acetaminophen administration was treated with morphine and vice versa.
Duration of analgesia was defined as the time from completion of block injection (time zero) to first administration of acetaminophen or morphine. At 24 h postoperatively, cumulative analgesic consumption was noted.
Sensory and motor block were assessed as described above. Offset of sensory block in the femoral and LFC nerve distributions was defined as return to normal sensation. Offset of obturator motor block was defined as return to normal adductor power. Persistence of sensory or motor block at 24 h was recorded as offset at 24 h. Adverse effects—bradycardia, intraoperative ephedrine requirements, preoperative and postoperative hypotension, epidural spread, nausea/vomiting—or block-related effects (infection, neuropathy) were noted.
Based on = 0.05, ß = 0.2 and seeking a difference of 4 hours (6) in the time to first supplementary analgesic administration with an estimated standard deviation of 4 h, a sample size of 12 per group was required for one-tailed testing.
Statistical analysis was performed with GraphPad Prism version 4.00 for Windows, (GraphPad Software, San Diego, CA; www.graphpad.com). Continuous parametric data were analyzed using one-way analysis of variance. Bonferroni’s multiple comparisons test was used for post-testing. Nonparametric data were analyzed using Kruskal-Wallis test with Dunn’s test for posttesting. Proportional data were analyzed using Fisher’s exact test. Data presented as mean ± sd or medians (range). P < 0.05 was taken as statistically significant.
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Results |
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The three groups were similar in terms of age, gender, weight, ASA physical status, and surgery type. The groups were similar in terms of preoperative and intraoperative fentanyl usage, sevoflurane ET%, and 24 h cumulative morphine and acetaminophen consumption (Table 1).
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The interval from time of completion of block injection to first supplementary analgesic administration was longer in group IC compared with group L (mean ± sd, 13.4 ± 6.1 versus 7.3 ± 3.6 h; P = 0.03). No difference was found between group C and group L (10.3 ± 5.9 versus 7.3 ± 3.6 h; P > 0.05).
The onset of sensory block in the femoral and LFC nerve distributions and obturator motor block was similar in the three groups as shown in Table 2. Thermoanesthesia at 45 min was partial in the femoral nerve distribution in three patients (1 in group C, 2 in group IC) and of the LFC nerve distribution in two patients (group IC). Seven patients (3 in group L, 2 each in groups C and IC) failed to achieve complete adductor paralysis by 45 min; all except one (group L) did so at 3 h. These patients were excluded from onset but not duration of block analysis.
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Pain scores at rest or on movement were similar among groups except at rest on 24 h when group IC had a lower pain score than group C, P = 0.02 (Table 3).
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Sedation scores at each time point, detailed in Table 4 were similar.
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Adverse effects including intraoperative hypotension, indicated by ephedrine requirements, were also similar in terms of nature and incidence in the three groups (Table 5).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The most important finding of this study is that IV, but not perineural, administration of clonidine (1 µg/kg) prolonged the duration of analgesia of PCB with 0.5% levobupivacaine in patients undergoing hip fracture surgery.
Perineural clonidine is administered as an adjunct to peripheral nerve blocks to prolong the duration of local anesthetics (4). Clonidine inhibits C-fiber conduction in the rabbit vagus nerve. These effects require supraclinical concentrations, although clonidine enhances lidocaine’s LA effect at much smaller concentrations (10).
A microdialysis study by Kopacz and Bernards (11) suggests that in humans clonidine’s prolongation of lidocaine’s LA effect is also in part pharmacokinetic. The addition of 10 µg/mL of clonidine to lidocaine 1% resulted in reduced cutaneous blood flow and smaller tissue concentrations of lidocaine as compared with plain lidocaine. These effects lasted 40–60 minutes but were sufficient to prolong lidocaine sensory blockade by 2–3 hours.
In clinical practice the addition of 150 µg clonidine to 40 mL mepivacaine 1% with epinephrine prolongs duration of anesthesia and analgesia of axillary brachial plexus block for hand surgery (5). Perineural clonidine added to lidocaine 1% for brachial plexus block also prolongs postoperative analgesia and sensory but not motor block after upper limb surgery (12). The selective perineural administration of 50 µg clonidine with 10 mL mepivacaine 1.5% to median and musculocutaneous nerves for midhumeral block by Iskandar et al. (13), demonstrated prolongation of sensory block compared with blockade of the radial and ulnar nerves with 10 mL mepivacaine 1.5% alone.
However, in a study comparing the effects of 150 µg clonidine combined with 40 mL mepivacaine 1%, bupivacaine 0.5%, or ropivacaine 0.75% for axillary brachial plexus block, prolongation of blockade was only seen with mepivacaine and bupivacaine. Erlacher et al. (14) suggest that ropivacaine’s intrinsic vasoconstricting properties may negate clonidine’s pharmacokinetic effect.
Our study failed to demonstrate prolongation of anesthesia or analgesia by perineural clonidine in PCB. There are a number of possible mechanisms for our findings. First, clonidine may not prolong levobupivacaine’s action, as levobupivacaine is similar to ropivacaine in having intrinsic, although weaker, vasoconstrictive activity (9). These vasoconstrictive properties may negate clonidine’s vasoconstrictor activity and explain levobupivacaine’s longer duration of sensory block compared with racemic bupivacaine. Second, the concentration of clonidine we used (2.5 µg/mL) was less than previous studies and may have affected clonidine’s pharmacokinetic effects (5,11). Singelyn et al. (15) demonstrated that although 0.1 µg/kg clonidine with 40 mL mepivacaine 1% prolonged analgesia for brachial plexus block, it required a dose of 0.5 µg/kg or more to significantly prolong both analgesia and anesthesia. A smaller dose was used in our patient population because of concerns regarding the possible adverse hemodynamic effects of larger clonidine doses (16).
Finally, the inconsistency of our result with these studies may be a result of the exact site of administration of the clonidine. The PCB involves the administration of LA in proximity to the femoral nerve but with spread to the LFC and obturator nerves (2). The spread of LA is therefore within the psoas muscle rather than being confined to a neural sheath. This physical dispersion of solution may further affect local neural clonidine concentrations with consequent reductions in its direct neural and vasoconstrictor effects. In accordance with our results, Gerhardt et al. (17) also found no increase in analgesic duration with perineural clonidine in their study that compared 4 methods including PCB (30 mL ropivacaine 0.5%) with and without perineural clonidine (2 µg/kg) for postoperative analgesia after total knee arthroplasty.
The presence of 2 receptors in the substantia gelatinosa of the dorsal laminae of the spinal cord (18) as well as in the locus ceruleus of the midbrain (7) indicate alternative sites of analgesic action for clonidine. Previous peripheral nerve block studies using IM (5) or subcutaneous (16) clonidine to assess possible supraspinal mechanisms failed to demonstrate any additional analgesic effect. Clonidine causes vasoconstriction in subcutaneous adipose tissue (19) and skeletal muscle mainly via postsynaptic 2B but also 1 receptors (20), and local deposition may alter its pharmacokinetics. We demonstrated that clonidine administration did not prolong anesthesia in our patients, supporting a supraspinal analgesic action rather than a local anesthetic effect in this setting.
The pharmacokinetics of clonidine administered into the psoas muscle are unknown. There is rapid systemic absorption of bupivacaine after PCB with arterial concentrations being comparable to those after epidural and intercostal administration. However, the addition of epinephrine to bupivacaine results in significantly smaller arterial plasma concentrations (21). The plasma concentrations of clonidine after administration in PCB may therefore have been less than those seen in the IV clonidine group as a result of clonidine’s vasoconstrictive properties. Smaller plasma concentrations may explain why clonidine administered into the psoas muscle did not result in a significant increase in analgesic duration similar to that seen with IV clonidine.
The effects of IV compared with perineural clonidine in regional anesthesia have only been investigated for neuraxial blocks. Intravenous and caudal clonidine (2 µg/kg) provided similar periods of postoperative analgesia in children undergoing hypospadias repair (8). Bupivacaine spinal anesthesia is also prolonged by IV clonidine (3 µg/kg) (22). After a bolus of 8 µg/kg clonidine, plasma concentrations are larger after IV compared with epidural administration at 15 and 30 minutes (23). The analgesic effects of neuraxial clonidine may, however, be mediated at a spinal rather than supraspinal level. Cerebrospinal fluid concentrations of clonidine are 100–1000-fold larger after neuraxial than IV administration (23), which could explain why analgesia and plasma clonidine levels after epidural use do not correlate well (24).
The population we studied is the oldest in which the effects of clonidine in regional anesthesia have been investigated. Clonidine’s possible adverse effects on arterial blood pressure and heart rate are of particular concern in this age group because of their frequent incidence of cardiovascular disease. We found no difference in the incidence of adverse effects among groups. The incidence of preoperative hypotension was not statistically different (4 patients in group IC versus 1 each in groups L and C); however, a sample size of 129 patients would be required to detect this difference with a significance of 95% with 80% power. Administration of IV clonidine at a slower infusion rate may reduce this incidence.
Despite increasing the duration of postoperative analgesia with IV clonidine there were no differences among groups in terms of analgesic requirements or pain scores. The 6-hour duration of pain relief is similar to the fixed intervals for analgesic administration in our study, and the use of patient-controlled analgesia (PCA) may have permitted more precise morphine titration. Institutional ward policy and our previous experiences with PCA in this surgical group were reasons for not using this method. Except for VRS at rest at 24 hours, where there was a statistical but nonclinical difference between groups IC and C, no differences were found for VRS between groups. The use of visual analog scores may have permitted better definition of pain but it has proved to be impractical in this surgical population (25). The increased pain-free interval may improve sleep, patient satisfaction or reduce nursing pain relief interventions. A weakness of our study is that these possible additional benefits were not addressed.
In conclusion, the administration of IV, but not perineural clonidine (1 µg/kg) with PCB prolonged postoperative analgesia after surgery for traumatic hip fractures without increasing the incidence of postoperative adverse effects.
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References |
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- Stevens RD, Van Gessel E, Flory N, et al. Lumbar plexus block reduces pain and blood loss associated with total hip arthroplasty. Anesthesiology 2000;93:115–21.[Web of Science][Medline]
- Capdevila X, Macaire P, Dadure C, et al. Continuous psoas compartment block for postoperative analgesia after total hip arthroplasty: new landmarks, technical guidelines, and clinical evaluation. Anesth Analg 2002;94:1606–13.
[Abstract/Free Full Text] - Liu SS, Salinas FV. Continuous plexus and peripheral nerve blocks for postoperative analgesia. Anesth Analg 2003;96:263–72.
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- Eledjam JJ, Deschodt J, Viel EJ, et al. Brachial plexus block with bupivacaine: effects of added alpha-adrenergic agonists: comparison between clonidine and epinephrine. Can J Anaesth 1991;38:870–5.[Web of Science][Medline]
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- Bernard JM, Macaire P. Dose-range effects of clonidine added to lidocaine for brachial plexus block. Anesthesiology 1997;87:277–84.[Web of Science][Medline]
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[Abstract/Free Full Text] - Erlacher W, Schuschnig C, Koinig H, et al. Clonidine as adjuvant for mepivacaine, ropivacaine and bupivacaine in axillary, perivascular brachial plexus block. Can J Anaesth 2001;48:522–5.[Web of Science][Medline]
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- Culebras X, Van Gessel E, Hoffmeyer P, Gamulin Z. Clonidine combined with a long acting local anesthetic does not prolong postoperative analgesia after brachial plexus block but does induce hemodynamic changes. Anesth Analg 2001;92:199–204.
[Abstract/Free Full Text] - Gerhardt MA, Schlossberg ML, Reilley T. Spinal anesthesia ± intrathecal morphine versus peripheral nerve block ± clonidine for pain control after total knee arthroplasty [abstract]. Anesthesiology 2002;96:A884.
- Kawasaki Y, Kumamoto E, Furue H, Yoshimura M. 2 adrenoceptor-mediated presynaptic inhibition of primary afferent glutamatergic transmission in rat substantia gelatinosa neurons. Anesthesiology 2003;98:682–9.[Web of Science][Medline]
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- Essen EJ, Bovill JG, Ploeger EJ, Houben JJG. Pharmacokinetics of clonidine after epidural administration in surgical patients: lack of correlation between plasma concentrations and analgesia and blood pressure changes. Acta Anaesthesiol Scand 1992;36:300–4.[Web of Science][Medline]
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