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Anesth Analg 2001;92:199-204
© 2001 International Anesthesia Research Society


REGIONAL ANESTHESIA AND PAIN MEDICINE

Clonidine Combined with a Long Acting Local Anesthetic Does Not Prolong Postoperative Analgesia after Brachial Plexus Block but Does Induce Hemodynamic Changes

Xavier Culebras, MD, Elisabeth Van Gessel, MD, Pierre Hoffmeyer, MD, and Zdravko Gamulin, MD

Division of Anesthesiology, Geneva University Hospitals, Geneva 14, Switzerland

Address correspondence and reprint requests to Dr. X. Culebras, Division of Anesthesiology, Geneva University Hospitals, 24, Rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland. Address e-mail to xavier.culebras{at}hcuge.ch


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Clonidine in brachial plexus block prolongs analgesia of local anesthetics of short and intermediate duration. We performed a prospective randomized double-blinded study to determine the efficacy and adverse effects of clonidine mixed with a long-acting local anesthetic on postoperative analgesia. Sixty adult patients underwent elective rotator cuff repair using interscalene brachial plexus block combined with general anesthesia and were randomly divided into one of the following three groups. Placebo (n = 20): interscalene block with 40 mL of 0.5% bupivacaine with epinephrine (1/200000) and 1 mL of 0.9% saline, completed by 1 mL of 0.9% saline IM in the controlateral shoulder; Control (n = 20): interscalene block with 40 mL of 0.5% bupivacaine with epinephrine and 1 mL of 0.9% saline, completed by 150 µg (=1 mL) of clonidine IM; Clonidine (n = 20): interscalene block with 40 mL of 0.5% bupivacaine with epinephrine and 150 µg (=1 mL) of clonidine, completed by 1 mL of 0.9% saline IM. During anesthesia hemodynamic variables and fractional expired isoflurane concentration (FeISO) were recorded. The following postoperative variables were assessed: duration of interscalene block, quality of pain relief on a visual analog scale, side effects, and consumption of morphine with a patient-controlled analgesia device over 48 h. Patient characteristics were comparable. During anesthesia mean arterial pressure, heart rate, and FeISO were significantly decreased in Clonidine and Control groups compared with Placebo group. Duration of analgesia, defined as the time elapsed from interscalene injection to the first morphine request, was 983 ± 489 min in the Placebo, 909 ± 160 min in the Control, and 829 ± 159 min in the Clonidine groups. Pain scores and consumption of morphine at 24 h and 48 h showed no differences among the three groups. We conclude that adding 150 µg of clonidine in interscalene block does not prolong analgesia induced by 40 mL of bupivacaine 0.5% with epinephrine, but decreases mean arterial blood pressure and heart rate.

Implications: Clonidine in brachial plexus block does not improve postoperative analgesia when mixed with a long-lasting anesthetic. Nevertheless, with or without clonidine, bupivacaine in interscalene block provides a long-lasting analgesia of approximately 15 h.


    Introduction
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Major shoulder surgery is a painful procedure requiring an intensive management of postoperative pain. After these surgical procedures analgesia can be provided by an interscalene brachial plexus block (1) or with an IV opioid delivered with a patient-controlled analgesia (PCA) device. Interscalene brachial plexus block is superior to PCA in the management of postoperative pain after major shoulder surgery (2). Analgesia with interscalene block can be obtained either by a continuous infusion of a local anesthetic through a catheter (1,2) or with a single injection using a long-acting local anesthetic (3). To prolong a single dose of a local anesthetic, additives such as opioids or {alpha}2 adrenergic agonists such as clonidine have been advocated (38).

Whereas morphine does not improve analgesia when mixed with bupivacaine in interscalene block (3), data on the effect of clonidine added to bupivacaine are scarce. However, different authors have shown that clonidine prolongs the duration of analgesia of short or intermediate local anesthetics in brachial plexus block (48). The aim of this study was to evaluate in a double-blinded randomized fashion the effects of adding clonidine to a solution of 40 mL of 0.5% bupivacaine with epinephrine on postoperative analgesia characteristics of an interscalene block in patients undergoing shoulder surgery.


    Methods
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 Abstract
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 Methods
 Results
 Discussion
 References
 
The study was approved by the hospital Ethics Committee. Sixty adults, ASA physical status I-III, were recruited after obtaining written informed consent. All patients underwent elective rotator cuff repair using interscalene block combined with general anesthesia. The surgery was performed in a semi-sitting position using a standardized surgical procedure. Exclusion criteria were the following: ASA physical status IV, inability to understand the requirements of the protocol for reasons of language or intellect, opioid or clonidine therapy in the preoperative period, or existence of a peripheral neuropathy. Likewise, patients presenting contraindications to interscalene block, such as allergies to one of the study solutions, local cutaneous infection, or clotting disorders were not included in the study.

Patients were randomized in a double-blinded fashion to one of three groups using a sealed envelope system. Drug solutions were prepared by an anesthetist not involved in the performance of interscalene block, in patient care, or in data collection. Patients received midazolam 7.5 mg orally as premedication. On arrival in the operating room, standard monitoring of vital signs was instituted (electrocardiogram, noninvasive measurement of blood pressure, and pulse oximetry). A 17-gauge venous cannula was placed in the nonoperated arm.

Interscalene block was performed with the patient awake and positioned according to the method described by Winnie and Collins (9). A 23-gauge short-bevel 60-mm needle was used (Pole®, Cotop Int, Amsterdam, Netherlands), connected to a nerve stimulator, which was set to deliver impulses of 0.2–0.5 mA (frequency 1 Hz, 50–500 ms). The needle was considered to be placed correctly when contraction of either the biceps or muscle groups in the forearm was seen in response to stimuli between 0.2–0.4 mA; after aspiration to exclude intravascular placement, the local anesthetic mixture was injected. Forty mL of bupivacaine 0.5% with epinephrine (1/200000) was administered in all patients, who were randomized into the three following groups:

Placebo: 20 patients received the local anesthetic solution mixed with 1 mL of 0.9% saline, completed by 1 mL of 0.9% saline injected IM in the contralateral shoulder.

Control: 20 patients received the local anesthetic solution mixed with 1 mL of 0.9% saline, completed by 150 µg (1 mL) of clonidine injected IM in the contralateral shoulder.

Clonidine: 20 patients received the local anesthetic solution mixed with 150 µg of clonidine (1 mL), completed by 1 mL of 0.9% saline injected IM in the contralateral shoulder.

The quality of block was assessed every 5 min for 15 min after injection. Sensory block was evaluated by the temperature test using an ether-soaked swab. The onset time was defined as the time between injection and complete loss of cold perception in the C4 and C5 dermatomas. Motor block was defined as complete if the patient was unable to elevate his arm against gravity, partial if motor force was diminished but not totally absent, and failed if motor force was conserved.

General anesthesia was then induced in all patients using a standard procedure: fentanyl 0.1 mg was injected followed by sodium thiopentone at a dose of 3–5 mg/kg. Neuromuscular blockade was achieved with vecuronium 0.1 mg/kg and the trachea intubated. Anesthesia was maintained with isoflurane and nitrous oxide 60%–70%. The patients were placed in semi-sitting position approximately 15 min after induction, and surgery started 15 min later. Heart rate, peripheral oxygen saturation, fractional inspired oxygen concentration, fractional expired carbon dioxide concentration, and fractional expired isoflurane concentration (FeISO) were controlled continuously and arterial pressure was measured every 5 min. The anesthetist in charge assessed hemodynamic changes and adjusted the anesthetic by varying the FeISO and administering supplemental fentanyl at a dose of 0.1 mg only if the pulse rate and/or the mean arterial pressure increased 30% greater than resting values with a maximum end-expiratory isoflurane concentration of 1%. If systolic blood pressure was <90 mm Hg, or when the decrease of baseline mean arterial pressure was more than 30%, ephedrine 5 mg IV was administered. Bradycardia was defined as a decrease in heart rate to <60 bpm, and atropine (0.5 mg) IV was given in cases of <45 bpm.

The following variables were assessed in the postoperative period:

Quality of block 30 min after extubation using previously described criteria.
Sedation score at 30 min after extubation and at 24 h by using the following scale: 1 = awake and alert; 2 = sedated, responding to verbal stimulus; 3 = sedated, responding to mild physical stimulus; 4 = sedated, responding to moderate or strong physical stimulus; and 5 = not arousable.
Pain score at 30 min after extubation, at appearance of shoulder pain indicating regression of interscalene block, at 48 h, by using a visual analog scale ranging from 0–100, where 0 indicated complete absence of pain and 100 the worst pain imaginable.
Duration of block, defined as the time elapsed from performance of interscalene block and appearance of pain in the operated shoulder requiring analgesia. Analgesia was delivered using a PCA device with morphine programmed as follows: morphine concentration at 1 mg/mL, bolus dose of 1 mg with a lockout at 5 min, and a maximal dose of 30 mg over 4 h. The patient was instructed to activate the PCA whenever they felt the need for pain medication and to call the nurse to document the time and the visual analog scale score.
Consumption of morphine at 24 h and 48 h was recorded.
Incidence of nausea and vomiting, which were treated with 1.25 mg of IV dehydrobenzperidol.
Satisfaction score at 24 h and 48 h was assessed by using a visual analog scale (0 = no satisfaction, 100 = maximal satisfaction).

Statistical analysis was performed using the prolongation of time of analgesia of bupivacaine as the main criterion. According to the power analysis, setting the {alpha} risk at 5% and the ß risk at 10% indicated a group size of 20, on the basis of a prolongation of analgesia of at least 30% (compared with placebo). Statistical analysis was performed using Statview 4.5 for Macintosh (Abacus Concepts Inc., Berkeley, CA). Data are presented as mean ± SD or median (range).

Continuous variables were compared with the analysis of variance test and ordinal data were analyzed by using the Kruskal-Wallis test or {chi}2 test as required. A P < 0.05 was considered significant.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
There were no significant differences in patient characteristics or in the duration of surgery among groups (Table 1). One interscalene block failed in the Clonidine group and was not considered for further analyses. None of the remaining patients required supplemental fentanyl during surgery. No difference in onset time, and in quality of sensory and motor blocks before surgery and in the recovery room was noted among the groups (Table 2). FeISO during surgery was significantly smaller in Clonidine and Control groups compared with placebo (Fig. 1 ). In addition, FeISO in the Clonidine group was significantly smaller compared with Control group (Fig. 1). Mean arterial pressure and heart rate were significantly decreased in Clonidine and Control groups compared with Placebo group (Figs. 2 and 3). There were significantly more patients in the Clonidine and Control groups than in Placebo group who needed ephedrine (11, 9, and 2, respectively) (P < 0.05). One patient in the Placebo group received atropine 0.5 mg IV because the heart rate was <45 bpm (no statistical difference). Duration of interscalene block, pain scores, and morphine consumption at 24 h and 48 h showed no differences among the three groups (Table 3). Three patients in the Control group and five patients in the Clonidine group had a sedation score of 3 in the recovery room (NS) and at 24 h, all remaining patients had a sedation score of 1. No difference was found in the incidence of postoperative nausea and vomiting among the three groups. Overall satisfaction of patients was similar at 48 h, respectively 80 ± 20, 78 ± 30, and 82 ± 25 in Placebo, Control, and Clonidine groups. No complications of interscalene block were noted.


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Table 1. Patient Characteristics and Duration of Surgery
 

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Table 2. Characteristics of Interscalene Brachial Plexus Block Before Induction and in Recovery Room
 


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Figure 1. Evolution of fractional expired isoflurane concentration (FeISO) during anesthesia in the three groups. There is a significant difference through time among the three groups. *P <0.05 Clonidine and Control groups compared with Placebo group. +P <0.05 Clonidine group compared with Control group. -15 = patients in semi-sitting position, 15 min before starting surgery. 0 = start of surgery.

 


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Figure 2. Evolution of mean arterial pressure during anesthesia in the three groups. Except for baseline values, there is a significant difference through time between the Clonidine and Control groups compared to the Placebo group (*P <0.05). B = Baseline before interscalene brachial plexus block. -15 = patients in semi-sitting position, 15 min before starting surgery. 0 = start of surgery.

 

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Table 3. Postoperative Analgesic Data Over 48 h
 


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Figure 3. Evolution of heart rate during anesthesia in the three groups. Except for baseline values, there is a significant difference through time between the Clonidine and Control groups compared to the Placebo group (*P <0.05). B = Baseline before interscalene brachial plexus block. -15 = patients in semi-sitting position, 15 min before starting surgery. 0 = start of surgery.

 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
We evaluated the analgesic and hemodynamic effects of 150 µg of clonidine mixed with 40 mL of bupivacaine 0.5% with epinephrine in interscalene block combined with general anesthesia for rotator cuff repair surgery. The results show that clonidine does not provide any advantage in terms of improvement in postoperative analgesia characteristics, mainly a prolonged effect of interscalene block. In addition, we observed that during anesthesia the patients receiving clonidine either by perineural or IM routes, presented a significant decrease in mean arterial pressure, heart rate and end-tidal isoflurane concentration compared with patients in Placebo group.

Combined anesthesia for shoulder surgery is a routine procedure at our institution, essentially for the security and comfort of patients because they are placed for surgery in a semi-sitting position with the head covered with sterile surgical drapes.

Despite the fact that the patients were operated using combined anesthesia whereas in other reports they were operated using brachial plexus block alone, we think that the comparison between previously published data and ours can be made. Indeed, the main end point of our study was the assessment of postoperative analgesia after interscalene block, and for all patients the duration of block largely exceeded the duration of surgery. Thirty minutes after extubation, recovery from general anesthesia was adequate to evaluate the pain scores in all patients.

The absence of any analgesic benefit observed in our patients is not in agreement with previously published reports that documented significant improvement of postoperative analgesia when clonidine was added to local anesthetic for brachial plexus block (48). Singelyn et al. (4), using a methodology similar to ours, investigated three groups of 10 patients who received 40 mL of mepivacaine 1% with epinephrine and showed that 150 µg of clonidine in axillary plexus block, but not subcutaneous clonidine, prolonged the postoperative pain-free period. In three dose-response studies with a placebo group but no control group, the authors demonstrated a dose-related analgesic effect of clonidine mixed with either 40 mL of mepivacaine 1% (5,7) or 40 mL of lidocaine 1% (6). The results of Eledjam et al. (8) and Gauman et al. (10) are less conclusive because these authors have compared admixtures of either clonidine or epinephrine to a local anesthetic without a placebo (local anesthetic alone) and without a control group.

The difference between our results and those published previously (48,10) can be mainly explained by the type and the concentration of the local anesthetic administered. These authors investigated local anesthetics of short or intermediate duration of action, which for placebo groups lasted less than four hours. Clonidine, because of a long elimination half-life (11), could have improved the analgesic efficacy of these solutions. In the present study, we used a large dose of a long-lasting local anesthetic (duration 15 h), which could have masked the effects of clonidine on the nerve block.

Another factor that may explain the observed differences in the prolongation of postoperative analgesia with clonidine is the type of surgery. The previous studies investigated mainly outpatients undergoing minor hand and forearm surgery associated with mild to moderate postoperative pain rarely requiring opioid analgesics. For these patients, clonidine prolonged the pain-free period when injected in the sheath. In contrast, our patients underwent rotator cuff repair, which induces severe postoperative pain and requires intensive analgesic medication.

Apart from type of surgery, intensity of pain is variable. Singelyn et al.(4,5), mixing clonidine with mepivacaine demonstrated a prolonged postoperative pain-free period; interestingly the authors observed that intensity of pain when it appeared was not modified by the administration of clonidine, the efficacy of which according to the authors remained to be confirmed for more painful procedures. In our study, apart from the lack of effect of clonidine in prolonging the postoperative pain-free period, no effect was observed on the intensity of pain when it appeared. Thus, we confirmed for painful procedures, the results observed by Singelyn et al. (4,5) for minor and moderate surgeries.

Many hypotheses have been proposed to explain the analgesic properties of clonidine on the peripheral nerve such as local vasoconstriction (4,8,10), a direct action on the nerve (1214), or a systemic effect (4,1516).

Actually, local vasoconstriction as the main mechanism of action of clonidine, leading to a decrease in the systemic absorption of the local anesthetic, has not been demonstrated according to Gaumann et al. (10). In our study, when comparing Placebo and Clonidine groups, both of which received bupivacaine with epinephrine, no difference in duration of analgesia was observed; thus our results do not support the hypothesis of an additional vasoconstriction action of clonidine.

Based on in vitro studies, a direct local anesthetic effect of clonidine on action potentials has been proposed (12). This hypothesis seems rather unlikely in clinical conditions because clonidine concentrations required to reduce the action potential amplitude were at least 15 times larger in these in vitro studies (12,13). Recently Sia et al. (17) used 150 µg of clonidine as the sole analgesic into the brachial plexus sheath and failed to demonstrate any postoperative analgesia after hand and forearm surgery.

However, Gaumann et al. (12,14) demonstrated in an isolated desheathed rabbit vagus nerve model that a small concentration of clonidine, which itself has no effect on the action potential, has a significant enhancing effect on C-fiber when mixed with lidocaine. More in vitro studies must be performed to define the possible interaction of clonidine with local anesthetic on peripheral nerves.

In a clinical study, to differentiate between a local and systemic effect of clonidine, a control group was added (4). In the present study, clonidine injected in interscalene block did not prolong postoperative analgesia or demonstrate a better opioid-sparing effect when compared with the IM group. However in our study, a possible systemic effect of clonidine cannot be excluded. Fifteen minutes before starting surgery (approximately 30 minutes after perineural or IM clonidine administration), a significant decrease in end-tidal isoflurane concentration, mean arterial pressure and heart rate were observed (Figs. 1–3). These findings suggest that clonidine injected in the brachial sheath is rapidly absorbed in the vascular compartment, the hemodynamic modifications observed being a consequence of clonidine’s central effects. We can only speculate about the amount of clonidine absorbed, but considering its high lipid solubility (11) and the significant hemodynamic effects produced, this amount could be important.

Among the studies investigating the association of clonidine with local anesthetics for brachial plexus block, some reported significant arterial hypotension (6,10) and/or bradycardia (7,10), whereas others did not (4,5,8). In the present study, general anesthesia associated with interscalene block could have accentuated the hemodynamic effects of clonidine, which can be deleterious in patients operated on in a semi-sitting position. Because our patients were operated on using combined anesthesia, the other relevant central effect of clonidine such as sedation could not be detected.

In conclusion, this study shows that 150 µg of clonidine added to a long-acting anesthetic in interscalene block does not prolong postoperative analgesia, does not reduce intensity of pain and does not decrease morphine consumption. Nevertheless, with or without clonidine, 40 mL of bupivacaine 0.5% with epinephrine provide a long-lasting analgesia of 15 h, particularly beneficial for patients having painful rotator cuff repair surgery. In addition, clonidine reduces mean arterial pressure and heart rate during anesthesia. The lack of analgesic benefit along with hemodynamic effects observed precludes us from recommending the use of clonidine in interscalene block when using a long-acting local anesthetic.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Tuominen M, Pitkanen M, Rosenberg PH. Postoperative pain relief and bupivacaine plasma levels during continuous interscalene brachial plexus block. Acta Anaesthesiol Scand 1987; 31: 276–78.[Web of Science][Medline]
  2. Borgeat A, Tewes E, Biasca N, Gerber C. Patient-controlled interscalene analgesia with ropivacaine after major shoulder surgery: PCIA vs PCA. Br J Anaesth 1998; 81: 603–5.[Abstract/Free Full Text]
  3. Flory N, Van-Gessel E, Donald F, et al. Does the addition of morphine to brachial plexus block improve analgesia after shoulder surgery? Br J Anaesth 1995; 75: 23–6.[Abstract/Free Full Text]
  4. Singelyn FJ, Dangoisse M, Bartholomée S, et al. Adding clonidine to mepivacaine prolongs the duration of anesthesia and analgesia after axillary brachial plexus block. Reg Anesth 1992; 17: 148–50.[Web of Science][Medline]
  5. Singelyn FJ, Gouverneur JM, Robert A. A minimum dose of clonidine added to mepivacaine prolongs the duration of anesthesia and analgesia after axillary brachial plexus block. Anesth Analg 1996; 83: 1046–50.[Abstract]
  6. Bernard J-M Marcaire Ph. Dose-range effects of clonidine added to lidocaine for brachial plexus block. Anesthesiology 1997; 87: 277–84.[Web of Science][Medline]
  7. Büttner J, Ott B, Klose R. Der Einfluss von Clonidinzusatz zu Mepivacain. Axillaire plexus brachialis-blockade. Anaesthesist 1992; 41: 548–54.[Web of Science][Medline]
  8. 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]
  9. Winnie AP, Collins VJ. The subclavian perivascular technique of brachial plexus anesthesia. Anesthesiology 1964; 25: 353–63.
  10. Gaumann D, Forster A, Griessen M, et al. Comparison between clonidine and epinephrine admixture to lidocaïne in brachial plexus block. Anesth Analg 1992; 75: 69–74.[Abstract/Free Full Text]
  11. Eisenach JC, De Kock Marc, Klimscha W. {alpha} 50-Adrenergic agonists for regional anesthesia. A clinical review of clonidine (1984–1995). Anesthesiology 1996:85:655–74.
  12. Gaumann DM, Brunet PC, Jirounek P. Clonidine enhances the effects of lidocaïne on C-fiber action potential. Anesth Analg 1992; 74: 719–25.[Abstract/Free Full Text]
  13. Butterworth JF, Strchartz GR. The {alpha} 2-adrenergic agonists clonidine and guanfacine produce tonic and phasic block of conduction in rat sciatic nerve fibers. Anesth Analg 1993; 76: 295–301.[Web of Science][Medline]
  14. Gaumann DM, Brunet PC, Jirounek P. Hyperpolarizing afterpotentials in C fibers and local anesthetic effects of clonidine and lidocaine. Pharmacology 1994; 48: 21–9.[Web of Science][Medline]
  15. Bernard J-M, Kick O, Bonnet F. Comparison of intravenous and epidural clonidine for postoperative patient controlled-analgesia. Anesth Analg 1995; 81: 706–12.[Abstract]
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  17. Sia S, Lepri A. Clonidine administered as an axillary block does not affect postoperative pain when given as the sole analgesic. Anesth Analg 1999; 88: 1109–12.[Abstract/Free Full Text]
Accepted for publication September 19, 2000.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2001 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press