The Enhancement of Sensory Blockade by Clonidine Selectively Added to Mepivacaine After Midhumeral Block

During the last few years, the α₂-adrenergic agonist clonidine has been extensively studied as an addition to general and regional anesthesia. Its addition to local anesthetics for peripheral nerve block prolongs the duration of both anesthesia and analgesia ⁽¹⁾. On the basis of data showing that a small dose of clonidine enhances the quality of peripheral blocks without prolonging motor block ⁽²⁾, we hypothesized that a 100-μg dose of clonidine added to mepivacaine selectively for the median and musculocutaneous nerves would increase selectively the duration of sensory block for these nerves during midhumeral block. This technique ^(3,4) allows each nerve to be blocked selectively at the midhumeral level by using a peripheral nerve stimulator. Therefore, we tested this hypothesis in a prospective, randomized, double-blinded study.

Methods

After informed consent and institutional approval, 58 ASA physical status I and II patients scheduled for elective hand surgery (Dupuytren’s disease, ablation of osteosynthesis material, or finger osteotomies) were initially prospectively enrolled to receive a midhumeral block. Patients with the following conditions were excluded from this study: chronic use of clonidine, history of allergic reaction to any of the study drugs, and peripheral neuropathies. All drug solutions were prepared by an anesthesiologist who was not involved in the administration of anesthesia, patient care, or data collection.

Patients did not receive any premedication, and no additional drugs were administered during the operation. Arterial blood pressure, heart rate, and hemoglobin oxygen saturation were recorded during the entire study. The block was performed in 5 ± 2 min as follows: after insertion of an IV catheter, the midhumeral block was performed by a single anesthesiologist experienced in the technique. An insulated 5-cm needle (Stimuplex; B Braun, Melsungen, Germany) was placed at the junction between the upper and middle third of the arm just against the brachial artery. To locate the median nerve, the needle was inserted tangentially to the skin between the brachial artery and the palpating finger. After median nerve blockade, the needle was reoriented so that its position became perpendicular to the operating table, just medial to the artery, and it was advanced to locate and anesthetize the ulnar nerve. The needle was reoriented again so that its tip was placed perpendicularly to the arm just under the biceps muscle to locate and anesthetize the musculocutaneous nerve. Thereafter, the needle was removed to a subcutaneous position and introduced so that its tip was placed behind the humerus where the radial nerve lies in a groove. Paresthesia was never intentionally sought.

A nerve stimulator (Stimuplex-Braun) was used to locate the nerves. The required position of the needle was determined when an output lower than 0.7 mA still produced a slight distal motor response characteristic of each of the nerves (the median nerve, flexion of the wrist and the fingers; the radial nerve, extension of the fingers; the musculocutaneous nerve, flexion of the forearm; and the ulnar nerve, opposition of the thumb).

The patients were randomly allocated into two groups by using a computer-generated randomization list. The Control group (n = 28) received 10 mL of plain mepivacaine 1.5% for each nerve (the median, the musculocutaneous, the ulnar, and the radial). The Clonidine group (n = 30) received 10 mL of plain mepivacaine 1.5% for each nerve with the addition of 50 μg clonidine to the median and the musculocutaneous nerves. Patients with a failed block were excluded from the study. Failure was defined as inadequate regional anesthesia in the distributions of any nerves anesthetized, requiring the use of local supplementation or general anesthesia.

Blood samples from 10 patients in each group were drawn from a peripheral vein 20 min after the administration of the block. The blood was centrifuged and then frozen, and plasma was analyzed for mepivacaine concentrations by using gas chromatography.

Time to perform the block was defined as the time between the initial insertion of the insulated needle in the skin and its removal. Onset time for complete sensory block, defined as the time between injection and complete thermoanesthesia (ice), was recorded every 30 s for each nerve by an observer blinded to the anesthetic solution. After surgery, the durations of sensory and motor blockade were checked every 15 min for each nerve. Duration of sensory block was defined as the time from a complete block to restoration of temperature sensation (ice) for each cutaneous nerve distribution. Duration of the motor block was defined as the time interval between the occurrence of a complete motor block and the recovery of motor function for each nerve. The anesthesiologist who evaluated the sensory and motor blocks was blinded to the drug used.

Data were analyzed by using SAS 6.12 software (SAS Institute, Cary, NC). Quantitative anthropometric data, duration of surgery, and onset times of anesthesia in the different nerve distributions were expressed as mean ± sd and compared by use of t-tests. The duration of sensory and motor block was analyzed with Kaplan-Meier estimates and compared between groups by using the log-rank test. A P value <0.05 was considered significant.

Results

Initially, 58 patients were included in the study. Local anesthetic supplementation was performed at the elbow in one patient in the Control group and two patients in the Clonidine group. Those patients were therefore excluded from the analysis. The Control group (n = 27) and the Clonidine group (n = 28) were similar with respect to age (44 ± 10 vs 43 ± 9 yr), weight (72 ± 12 kg), male/female ratio (17:10 vs 19:9) and duration of surgery (40 ± 12 vs 45 ± 9 min).

Onset times for complete sensory block in the different nerve distributions were not significantly different between the two groups (Table 1).

The median duration of sensory block is shown in Table 2. In the Clonidine group, we observed a significant increase in the duration of sensory block in only the median and musculocutaneous nerves. For the median nerve, the median sensory block was 235 min (95% confidence interval [CI], 195–250) in the Clonidine group, compared with 150 min (95% CI, 135–160) in the Control group. For the musculocutaneous nerves, the median sensory block was 240 min (95% CI, 210–240) in the Clonidine group, compared with 145 min (95% CI, 135–150) in the Control group. The duration of sensory block in the radial and ulnar nerves was not significantly different when compared with that of the Control group. Recovery of motor block was not different between the groups (Table 3). Similarly, no significant differences were found in the mean plasma mepivacaine concentrations in the Control and Clonidine groups (3.48 ± 0.83 μg/mL and 3.49 ± 1.83 μg/mL, respectively). Although a mepivacaine concentration of 8.23 μg/mL was recorded in one patient, no clinical signs of local anesthetic toxicity were observed. No side effects related to the use of clonidine (sedation, bradycardia, or hypotension) were noted.

Discussion

The midhumeral block technique allows the performance of selective peripheral nerve blocks by using a nerve stimulator and application of different local anesthetics or drugs to each of the four nerves ^(4,5). Recently, Carles et al. ⁽⁶⁾, in a prospective study (1417 blocks), demonstrated that midhumeral block is a reliable peripheral block that allows frequent success rates.

The selective application of clonidine to only the median and the musculocutaneous nerves allowed comparison of their block characteristics with those of the ulnar and radial nerves. The results of this randomized, double-blinded study show that the addition of 50 μg of clonidine to the local anesthetic for median and musculocutaneous nerve blockade results in a significant increase in the duration of sensory block in these nerves. However, the duration of sensory block in the ulnar and radial nerves was not increased. This suggests a direct peripheral action of clonidine, because a central effect would have led to an increase in the duration of anesthesia in all four nerves. Moreover, signs of systemic uptake of clonidine, such as sedation, bradycardia, and arterial hypotension, were not observed.

We preferred to measure the duration of sensory block rather than to measure the duration of analgesia and pain scores because the former specifically reflects the characteristics of the block in each nerve, whereas the latter postoperative scores do not. In effect, the postoperative administration of analgesics relieves all pain irrespective of the particular nerve territory, but we wanted to evaluate the block in specific nerves.

The addition of clonidine to the median and musculocutaneous nerves did not prolong the motor block in this study. This is in agreement with Bernard and Macaire ⁽²⁾, who demonstrated that a small dose of clonidine (30–90 μg) enhances the quality of peripheral blocks without prolonging motor block. Such a finding would have interesting clinical applications, particularly in outpatient surgery, where patients operated upon with peripheral block anesthesia can leave the hospital setting while pain free and after quick and complete recovery of motor function. Moreover, after tendon suture of the hand or wrist in the surgery, the selective lengthening of sensory block by applying clonidine allows the patient to begin pain-free physiotherapy.

The selection of the optimal long-acting local anesthetic or the novel analgesic adjuncts to peripheral block must take into consideration the available anesthetics, the duration of sensory and motor block, the side effects of each drug, and dose. Davis et al. ⁽⁷⁾ used a long-acting local anesthetic in outpatients. No adverse effects were reported in patients discharged with a partial motor and sensory block who had previously been advised to exercise caution until the sensory block had worn off. Nevertheless, motor block is undesirable in the postoperative period because partial motor block impairs control of movements and may increase the risk of injury. Therefore, different methods have been used after peripheral block anesthesia to prolong the duration of sensory and postoperative analgesia without prolonging the motor block.

• Martin et al. ⁽⁸⁾ used a mixture of lidocaine and bupivacaine for an axillary block. The duration of analgesia was shorter than bupivacaine, with increasing analgesic requirements.
• Bouaziz et al. ⁽⁹⁾ selectively administered different local anesthetic solutions after midhumeral block for outpatient hand surgery. This sensory-motor block separation allowed earlier discharge from the hospital.
• Clonidine adjunct for plexus block: Singelyn et al. ⁽¹⁰⁾ reported that clonidine added to mepivacaine prolongs the duration of anesthesia and analgesia after axillary brachial plexus block without enhancement of motor blockade. For foot surgery, Casati et al. ⁽¹¹⁾ reported that the addition of 1 μg/kg clonidine to 0.75% ropivacaine after sciatic-femoral nerve block prolongs the duration of postoperative analgesia without hemodynamic adverse effects. This is particularly important after outpatient foot surgery, in which residual motor block may lead to falls.
• Adjunction of tramadol ⁽¹²⁾ and neostigmine ⁽¹³⁾ to local anesthetic: by using a metaanalysis, Murphy et al. ⁽¹⁴⁾ review current evidence of the efficacy of adding novel analgesic adjuncts to brachial plexus block. The authors reported that only clonidine appears to have significant analgesic benefit and to cause minimal adverse effects; data regarding tramadol and neostigmine are not sufficient to allow any recommendations, and further studies are required.

Concerning the mechanism of action of clonidine on peripheral nerves, Eisenach et al. ⁽¹⁵⁾, after a clinical review, agreed with a peripheral action of clonidine for regional anesthesia: the duration of anesthesia or analgesia was enhanced by clonidine added to the local anesthetic after plexus block ^(16,17), but not by subcutaneous and IM clonidine injections ^(18,19). Several hypotheses have been proposed to explain the mechanism of action of clonidine on peripheral nerves.

• Modification of the local anesthetic chemical composition: no significant change, i.e., pH and chemical were observed in the composition of the mixture when clonidine was added to lidocaine ⁽²⁰⁾.
• Modification of the local anesthetic pharmacokinetics: clonidine has no peripheral vasoconstrictive effect ⁽¹⁹⁾. In our study, no difference was found in the mean plasma concentrations of mepivacaine between the two groups. Measurement of serum mepivacaine at only 20 min after injection was insufficient to account for all the pharmacokinetic modification that could have occurred because of clonidine, but it did reflect the concentration peak for the two groups ⁽²¹⁾.
• Direct neuronal effects of clonidine: in an isolated rabbit vagus preparation, Butterworth and Strichartz ⁽²²⁾ and Gaumann et al. ⁽²³⁾ showed that a very small dose of clonidine enhances the effects of lidocaine on C-fiber action potentials.

Sia and Lepri ⁽²⁴⁾ used clonidine as the sole analgesic for axillary block. The authors concluded that the administration of clonidine alone through an axillary catheter did not enhance postoperative analgesia after hand and forearm surgery and that clonidine must be added to a local anesthetic to produce improvement in postoperative analgesia. However, the absence of efficacy in their study may be explained by the inability of clonidine administered through the axillary catheter to spread uniformly through the axillary sheath because of septa separating the nerves ⁽²⁵⁾. Therefore, there may have been an insufficient concentration of the drug at the level of the nerve fibers.

In conclusion, by selectively applying clonidine with local anesthetics in the midhumeral block technique, it is possible to prolong the duration of sensory block in one or several trunks of the brachial plexus. Additionally, our data support a specific effect of clonidine on peripheral nerves. This could have some interesting clinical implications, particularly in ambulatory surgery or in the planned repair of tendons in which motor function is best maintained.