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*Department of Anesthesiology and Intensive Care Medicine, Nancy University Hospitals, Department of Plastic and Hand Surgery, Hôpital Jeanne d’Arc, Department of Clinical Epidemiology and Evaluation, Marin Hospital, Nancy, France
Address correspondence and reprint requests to Professor Hervé Bouaziz, Service d’anesthésie-réanimation chirurgicale, Hôpitaux de ville, CHU de Nancy 29, Avenue du Maréchal-de-Lattre-de-Tassigny, 54035 Nancy Cedex, France. Address e-mail to h.bouaziz{at}chu-nancy.fr.
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Abstract |
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Introduction |
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) and C fibers at the site of inflammation. In addition, it increases the excitability of spinal cord neurons, which will amplify sensory inputs through central sensitization (1). Infected tissue surgery is associated with significant postoperative pain (88% with pro re nata analgesics and 21% with multimodal pain management) (2). A neural blockade of longer duration has been shown to avoid hyperalgesia phenomena in a rat model of inflammation (3). Thus, in the clinical setting of inflammatory tissue surgery, a better quality and a longer duration of the sensory block would be desirable.
The 
2-adrenergic agonist clonidine, when administered in combination with local anesthetics in axillary blocks (lidocaine, mepivacaine, bupivacaine)(4–6), has been shown to decrease sensory block onset time and prolong anesthesia after elective surgery. Doses up to 150 µg are associated with minimal side effects (7). No study evaluated the effects of adding clonidine to axillary brachial plexus block for infected tissue surgery, where a delay in onset of sensory block and significant postoperative pain may be encountered.
We hypothesized that the onset of sensory block is delayed in infected tissues compared with healthy areas within the same major nerve distribution and that clonidine 100 µg added to mepivacaine 1% would decrease the sensory block onset time in infected tissues and enhance postoperative analgesia.
To test this hypothesis, we performed a prospective randomized, double-blind, controlled clinical trial in patients undergoing incision and drainage of paronychia under axillary brachial plexus block with mepivacaine and clonidine or placebo.
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Methods |
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On arrival in the anesthesia induction room, standard monitoring was established (pulse oximetry, electrocardiography, and automated sphygmomanometry; Cardiocap II, Datex, Helsinki, Finland). A 20-gauge cannula was sited in a peripheral vein in the contralateral arm and oxygen was delivered via a Venturi face mask at a rate of 3 L/min. An axillary perivascular brachial plexus block was then performed by a single experienced anesthesiologist (SB) using a nerve stimulator (Stimuplex HNS 11, B/Braun, Melsungen, Germany). With the patient supine, with the arm at a 75° angle, abducted and externally rotated, a 50 mm 24-gauge insulated short bevel needle (Stimuplex® A 50, B/Braun, Melsungen, Germany) was inserted at a point high in the axilla, approximately 40 mm from the pectoralis major muscle insertion. The stimulation frequency was set at 2 Hz and the duration of stimulation at 0.1 ms. The intensity of the stimulating current, initially set to deliver 2 mA, was gradually decreased to <0.6 mA after the appropriate motor response was observed (thumb opposition for median, thumb abduction for radial, thumb adduction or ulnar deviation of the hand for ulnar, and flexion of forearm on the arm for musculocutaneous nerves). Increments of anesthetic mixture (9 mL/nerve in total) were injected through a stationary needle after identifying the four nerves in the following order: median, radial, ulnar, and musculocutaneous. The remaining 6 mL were instilled subcutaneously as the needle was withdrawn to block the intercostobrachial nerve. If anesthesia was insufficient after 40 min, one or more distal nerve blocks were performed and the patient was excluded and replaced in the randomization list.
Blocks were evaluated every 5 min in the first 40 min from the time of withdrawal of the needle (considered as time point T0). Sensory block was evaluated in the median and radial nerve distribution of the hand and in the infection area, using light touch with cotton wool: 0 = no perception, 1 = blunted sensation, 2 = normal sensation. In addition, a painful stimulus (squeezing of the fingertip) was applied directly to the infected area to assess the presence or absence of pain. Thus, the onset time of sensory block was defined as the time elapsed from the removal of the stimulating needle (end of injection) until the complete loss of sensory function in a specific territory.
Postoperatively patients were asked to note the time when paresthesia reappeared in the surgical area. Duration of sensory blocks was considered as the time interval between withdrawal of the needle and reappearance of paresthesia in either the median or the radial nerve distribution area. They were instructed to request an analgesic as soon as they first experienced pain after surgery.
Heart rate, systolic and diastolic arterial blood pressures, arterial oxyhemoglobin saturation, and sedation on a 5-point scale (0 = wide awake, 1 = drowsy, 2 = dozing intermittently, 3 = mostly asleep, 4 = only aroused by tactile stimulation) were documented every 5 min intraoperatively and every 30 min postoperatively until recovery from anesthesia. Patients were discharged from the hospital after block resolution.
Postoperative analgesia consisted of acetaminophen plus codeine (1g acetaminophen plus 45 mg codeine 8 hourly) and ketoprofen (75 mg 12 hourly) or tramadol (50 mg 8 hourly if there was a contraindication to NSAIDs). Time to first analgesic requirement (time elapsed between drug injection and the first analgesic request) and visual analog scale (VAS) scores (graded from 0 = no pain to 100 = unbearable pain) were recorded at this time. Pain was also evaluated via telephone interview at 24 and 48 h using a 10-point verbal rating scale graded from 0 (no pain) to 10 (worst imaginable pain). In case of inadequate analgesia at home, patients were asked to contact the anesthesiologist by telephone for rescue medication.
Side effects and their management were defined as follows: a) hypotension: a decrease of more than 25% of mean systemic arterial blood pressure compared with baseline values, managed by increments of ephedrine 3 mg IV every 2 min; b) bradycardia: heart rate <45 bpm, managed by a 0.5 mg IV bolus of atropine; c) sedation: 3 or more episodes of Spo2 equal or <90% within a 3 min period, warranting increasing the oxygen flow to 6 L/min.
In the absence of historical data, the number of patients needed for this study was estimated based on a pilot study of 16 patients with paronychia. Clonidine added to mepivacaine decreased the axillary brachial plexus block onset time in the infected area from 25 ± 7 min to 10 ± 3.4 min compared with placebo. It was calculated that a minimum of 28 patients (14 pairs) would be required to have an 80% power of detecting a 50% reduction in the onset time at a significance level of 0.05.
Data on patient demographics were analyzed using Fisher’s exact test (
2) for the qualitative and Wilcoxon’s test for the quantitative data. Analysis of variance-covariance (Wilcoxon’s test) was used to compare parametric and Kruskal-Wallis or 2 test, as required for nonparametric variables between groups. P < 0.05 was considered significant. Two-sided significance tests were used throughout.
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Results |
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The two groups (clonidine, n = 21 and placebo, n = 20) were similar in terms of age, gender, weight, height, and ASA class (Table 1). Before the block, all patients had normal sensory perception in the operated limb. Duration of surgery, hemodynamics, and Spo2 were not different between groups. No systemic effect of clonidine was noted.
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In the placebo group, onset of sensory block (tested for light touch) in the infected area was delayed compared to onset of sensory block in both the median and radial nerve distribution area (24.7 ± 5.5 min versus 21.3 ± 7.2 and 21.6 ± 7.8 min; P = 0.02 and P = 0.04, respectively) (Fig. 1).
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In the clonidine group, when tested for light touch in the area of surgery, sensory block onset time was decreased compared to placebo in the two nerve territories: median (9.8 ± 4.6 versus 21.3 ± 7.2 min; P < 0.001) and radial (11.2 ± 6.8 versus 21.6 ± 7.8 min; P = 0.002) (Fig. 1). No difference in the onset time of sensory block between infected and healthy tissues within the same nerve distribution was noted in the clonidine group.
In the clonidine group, anesthesia onset time in the infected area was decreased compared with placebo, whether tested for light touch (9.1 ± 1.9 versus 24.7 ± 5.5 min; P < 0.0001) or painful stimulus (9.0 ± 2.5 versus 27.5 ± 7.7 min; P < 0.0001) (Fig. 1).
The duration of sensory block was increased in the clonidine group compared with placebo (275 ± 75 versus 163 ± 57; P = 0.04). Similarly, the time interval to first analgesic requirement was prolonged in the clonidine group compared with placebo (279 ± 87 versus 197 ± 84 min; P = 0.002). VAS scores at the time of first analgesic requirements were decreased in the clonidine group compared with placebo (30 ± 18 versus 70 ± 24; P < 0.0001) (Table 2). Also, when taking the prescribed analgesics (acetaminophen and ketoprofen), verbal rating scores in the clonidine group were decreased compared with the placebo group at 24 (1.7 ± 2.2 versus 4.1 ± 3.0; P = 0.002) and 48 h (0.1 ± 0.5 versus 1.5 ± 2.4; P = 0.01), respectively (Table 2). No patient in either group required rescue analgesics.
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Discussion |
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The observation that peripheral nerve blocks provide poor anesthesia of a distal infected area is a novel phenomenon, the cause of which remains unknown. Although the 10% incidence of failure may be acceptable, this was reduced to nil when adding clonidine to mepivacaine in the present study. Onset of anesthesia was delayed in the infected area compared with healthy tissues within the same nerve distribution. One possible explanation lies with alterations in the nerve cell membranes and abnormal physiological responses in the presence of inflammation, of which paronychia is a classic example (8). This observation clearly deserves further research.
Our study findings are in agreement with others regarding the efficacy of clonidine added to mepivacaine in brachial plexus blocks for elective surgery (5,9). Similar to other studies, the multiple stimulation technique we used to perform the block served to eliminate bias (as a result of a different spread of the local anesthetic) and yielded more frequent success than stimulation of the median nerve alone. Also, the use of mepivacaine, a local anesthetic of relatively short duration, facilitated the detection of any clonidine effect in the postoperative period. In this study we chose a dose of clonidine (100 µg) that has been shown to produce maximal local effects without confounding variables attributable to systemic absorption (4).
In the absence of a valid method of evaluation of sensory blocks, a multitude of tests has been used in the past. Similar to other authors, we used a simple, reproducible, noninvasive method for evaluation of sensory block (4,5,10). Testing the various regions separately allows a more detailed evaluation of the efficacy of blocks. In addition, although this has not yet been validated, we opted to test the infection area separately (to light touch and painful stimulus) because of its immediate clinical implication.
Using paronychia as a model for infected tissue surgery provided us with a homogenous study population. Paronychia or whitlow, an inflammatory reaction involving the folds of the skin surrounding the fingernail, is one of the most common infections of the hand (11). It is characterized by acute or chronic purulent, tender and painful swelling of the tissues around the nail, caused by an abscess of the nail fold (11). Successful management of an uncomplicated infection requires an accurate diagnosis and prompt initiation of treatment, consisting of the judicious use of an appropriate incision, wound drainage, local wound care, and early rehabilitation (12). Regional anesthesia is a priori contraindicated in the proximity of infection (13); the axillary brachial plexus block is a widely accepted technique for anesthesia in patients with a localized and distal infection such as paronychia, provided signs and symptoms of lymphangitis or axillary adenopathy have been excluded. The nonrandomized, nonblinded nature of infected versus noninfected tissues (because of practical impossibility) may have introduced bias. However, the effect of clonidine was randomized and double-blind in the present study design.
The administration of adjuncts to local anesthetics in brachial plexus block must demonstrate prolonged analgesic efficacy over systemic administration, if they are to be useful in clinical practice (7). When added to mepivacaine 1%, clonidine repeatedly demonstrated a dose-dependent prolongation of duration of anesthesia, analgesia, and motor block (5,9,10,14). It is likely that prolongation of local anesthetic block occurs because of a combination of pharmacokinetic and pharmacodynamic effects on local anesthetic actions (15). Unfortunately, a control group receiving parenteral administration of the same dose of clonidine was not considered when designing our investigation. This study did not aim, however, at elucidating the mechanism of action of clonidine. Because of our positive results, the question of whether these results were attributable to a local or systemic effect warrants further investigation.
Clonidine has mixed 1 and 2 agonist effects at both presynaptic and postsynaptic receptors and effects on a number of other specific receptors. Its mechanism of action and effects, therefore, are likely to be compound and complex (16). However, when added to mepivacaine (14) or bupivacaine plus epinephrine (17), clonidine appears to prolong duration of anesthesia and postoperative analgesia by a local effect.
The difference in the onset of anesthesia between infected and healthy tissues disappears when clonidine is added to mepivacaine. The mechanism of action of clonidine added to local anesthetics in the presence of inflammation, as seen in our study, remains speculative.
Sensory nerve activity may be enhanced during inflammation as a result of interaction with inflammatory mediators leading to an increase in the electrical activity of sensory afferent nerves and an increase in neurotransmitter release from autonomic nerves and C-fiber nerve endings. Recent evidence suggests an important role for both A and C-fibers in the prolonged sensitization under inflammatory conditions (18). Clonidine blocks conduction of A and C-fibers, with some preference for C-fibers, and intensifies the conduction block of local anesthetics (19,20).
Another rationale for using clonidine for peripheral nerve blocks in the context of infected tissues lies with its antiinflammatory properties. Clonidine inhibited rat paw and brain edemas induced by various inflammatory agents (21), as well as ocular inflammation in pigmented rabbits (22), and these effects were prevented by yohimbine, as would be expected from their mediation through the stimulation of 2-adrenoreceptors. The analgesic effect is likely to be cumulative with antiinflammatory activity, whether related to inhibition of eicosanoid synthesis, noradrenergic or dopaminergic stimulation, or inhibition (direct or not) of various neuromediators such as serotonin or substance P. Further studies will be required to elucidate these possibilities.
An interesting finding of our study was the enhancement of postoperative analgesia in the clonidine group, well beyond the pharmacologic effect of either clonidine or mepivacaine. Direct modulation of the activity of sensory nerves could conceivably explain the difference in postoperative analgesia between the groups for up to 48 hours in our study. Alternatively, this could have been a result of an overall better quality of anesthesia at the time of surgery. Regardless of the mechanism, this is a valuable advantage in the clinical setting of infected tissue surgery.
In conclusion, we have demonstrated that infected tissues are resistant to regional anesthesia performed at a distance compared with healthy areas within the same nerve distribution. Clonidine 100 µg added to mepivacaine 1% decreases the onset time and prolongs the duration of anesthesia in the presence of infected tissues and enhances the quality of postoperative analgesia up to 48 hours after incision and drainage of paronychia. Thus clonidine added to axillary brachial plexus block with mepivacaine may be useful in the presence of a distal upper limb infection.
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Footnotes |
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Accepted for publication August 31, 2004.
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References |
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and C-fibres. Pulm Pharmacol Ther 2003;16:1–7.[ISI][Medline]
2-adrenergic mechanisms in experimental analgesic and anti-inflammatory activities of a benzamide derivative. Pharmacol Res 1997;36:179–85.[ISI][Medline]
2-adrenergic agonists on lipopolysaccharide-induced aqueous flare elevation in pigmented rabbits. Jpn J Ophthalmology 2001;45:221–6.This article has been cited by other articles:
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  K. E. Langen, K. D. Candido, M. King, G. Marra, and A. P. Winnie The Effect of Motor Activity on the Onset and Progression of Brachial Plexus Block with Bupivacaine: A Randomized Prospective Study in Patients Undergoing Arthroscopic Shoulder Surgery Anesth. Analg., February 1, 2008; 106(2): 659 - 663. [Abstract] [Full Text] [PDF]
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A. Movafegh, M. Razazian, F. Hajimaohamadi, and A. Meysamie Dexamethasone Added to Lidocaine Prolongs Axillary Brachial Plexus Blockade Anesth. Analg., January 1, 2006; 102(1): 263 - 267. [Abstract] [Full Text] [PDF]
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