Clonidine is an α2-adrenoreceptor agonist that has been shown to effectively prolong the duration of analgesia when administered intrathecally or in the epidural space (1–3) in children. The effect of clonidine on the duration of the sensory block after a peripheral nerve block in children has never been evaluated. Multiple studies have been conducted in the last decade on the use of clonidine in adults; however, it is difficult to extrapolate these data from the adult literature and apply them to the pediatric population, mostly because of the contradictory results of the published studies. Some studies have shown that clonidine prolongs the effects of lidocaine, bupivacaine, mepivacaine and ropivacaine (4–6). Others have disputed these findings (7–9). A common side effect reported in most of these studies is a prolonged motor blockade in patients who receive clonidine. A motor block can be troublesome for children and their families, and can be a source of accidents when affecting the lower extremities. Moreover, a neurologic examination is routinely performed in the recovery room after orthopedic procedures, to exclude significant neurologic deficits. A delayed recovery of motor function requires postponing this evaluation, thereby offsetting the potential advantages offered by prolonged sensory block in terms of early hospital discharge.
In this study, we have reviewed the clinical data collected prospectively from children who had a peripheral nerve block for postoperative analgesia. We hypothesized that the addition of clonidine to a local anesthetic would increase the duration of sensory block and/or the duration of analgesia.
The study was approved by The Children’s Hospital of Philadelphia IRB for Human Studies. We reviewed the regional anesthesia database and the medical records of children who had undergone a peripheral nerve block for postoperative analgesia at The Children’s Hospital of Philadelphia between October 2002 and December 2005. The regional anesthesia database contains medical information of children who undergo a peripheral nerve block, including demographic data, information on anesthetic and surgical techniques, and follow-up data. With respect to the patient’s follow-up evaluation, the initial physical examination is always conducted in the recovery room by nurse practitioners. The evaluation of patients admitted to the hospital is done by an anesthesiologist and clinical data (duration of sensory and motor blockade, vital signs, pains scores and opioid administration) are recorded by nurses every 4 h for the duration of the hospital stay. Patients discharged home are followed by nurse practitioners in the pain management service with daily or twice daily phone calls until resolution of sensory block or possible side effects. Parents were asked to record the duration of sensory block and intake of oral opioids during the follow-up period and to report these data to the interviewer. Patients who experienced a motor block in the immediate postoperative period were discharged from the hospital only after complete resolution of the motor block.
Patients who satisfied the following inclusion criteria were included in this analysis: 1) those who underwent one of the following nerve blocks: infraclavicular, lumbar plexus, femoral, sciatic, fascia iliaca; 2) those who had a single injection nerve block; 3) those in whom we were able to obtain a clinical follow-up until resolution of the sensory blockade. Subjects were excluded from the final analysis, if 1) they had peripheral nerve catheter or an intraarticular catheter for a continuous infusion of local anesthetic; 2) they were lost to follow-up; or 3) the peripheral nerve block failed. We considered a peripheral nerve block unsuccessful when we detected a persistent sensation on the entire or sections of the blocked extremity at the time of physical examination conducted in the immediate postoperative period.
Nerve blocks were performed after induction of general anesthesia, with the aid of a nerve stimulator. Eleven anesthesiologists had performed the peripheral nerve blocks during the study period. Two different local anesthetics, bupivacaine with epinephrine (1:200,000) (concentrations ranging between 0.1 and 0.25%) and plain ropivacaine, (concentrations ranging between 0.1 and 0.2%), were used, depending on the anesthesiologists’ preference. The dose of local anesthetic used in the femoral, fascia iliaca, lumbar plexus and infraclavicular nerve block was 0.5 mL/kg (max 40 mL). The same doses were used for sciatic nerve block, with a maximum dose of 20 mL. The addition of clonidine (1 μg/kg, max 100 μg) to the local anesthetic was randomly decided by the anesthesiologist in charge of the case. The original concentration of clonidine (Elan, King of Prussia, PA), as supplied by the pharmaceutical company was 500 μg/mL. This was diluted to a concentration of 50 μg/mL in normal saline, and the calculated dose was added to the local anesthetic.
The following data have been considered for final analysis: age, sex, type of peripheral nerve block, local anesthetic used, concentrations, type of surgery, duration of sensory and motor block, time to first dose of oral or IV opioids in the postoperative period, and presence of any complication such as paresthesia and/or dysesthesia. The duration of sensory blockade was determined by patients’ response to pinprick stimulation. When patients were discharged home before the resolution of the sensory blockade, the duration of sensory block was then defined as the time elapsed from the performance of the nerve block to the complete resolution of numbness in the extremity or area blocked. We excluded from analysis patients who were unable to place the time of return to normal sensation within 1 h of its occurrence. The duration of analgesia was defined as the time elapsed form the nerve block and the first consumption of IV or oral opioids. Motor blockade was defined as follows: 1) lower extremity: patient unable to raise the lower extremity and/or move their toes, depending on the type of nerve block performed; 2) upper extremity: patient unable to raise and/or move arm, forearm, hand and/or fingers, depending on the type of nerve block performed. Duration of motor block was defined as the time elapsed from performance of the nerve block to full recovery of motor function of the blocked extremity. No patient was discharged from the hospital until complete resolution of motor blockade.
Normal distribution of the data was verified with Kolmogorov–Smirnov test. Continuous variables were analyzed using Student’s t-test for unpaired data or Mann–Whitney U-test based on data distribution. Categorical variables were analyzed using contingency tables analysis and χ2 test. Univariate and multivariate linear regression models were fitted to relate the duration of sensory block to possible predictors. The following variables were analyzed in the regression: age, sex, type of peripheral nerve block, use of clonidine, physician who performed the block, type of local anesthetic and concentration. A stepwise logistical regression was performed to identify independent variables that could predict the duration of sensory block.
A total of 531 patients underwent a single-shot peripheral nerve block for postoperative analgesia at The Children’s Hospital of Philadelphia in the study period. Fifty-two patients (9%) were excluded from analysis because the block was totally or partially unsuccessful as determined by a neurologic examination in the recovery room. Sixty-four (12%) additional patients were excluded because of incomplete long-term follow-up, including patients who were unable to report the time of numbness resolution. Of the remaining 415 patients, 220 received a combination of a local anesthetic and clonidine (LAC) and 215 received a local anesthetic only (LA). There was no difference between groups with respect to gender distribution and age (Table 1).
Two hundred eighty-one patients (68%) were admitted for at least 24 h after the operation and their follow-up was completed by an anesthesiologist. The remaining 134 patients (32%) were discharged home within a few hours after the operation. The duration of sensory blockade was significantly longer in the LAC group (17.2 ± 5 h) compared with that in the LA group (13.2 ± 5 h) (P = 0.0001). We observed an increase in sensory blockade duration in every type of peripheral nerve block when clonidine was added to the local anesthetic (Table 2). The effects of clonidine on sensory blockade were more pronounced when combined with lower concentrations of local anesthetics (Table 3). The duration of analgesia was significantly longer in the LAC compared with that in the LA group (10 ± 7 vs 6.8 ± 6 h) (P = 0.0008). However, there was no difference in the number of patients who required opioids after surgery (65 vs 59%, P = 0.27) between groups. The two groups were also similar when considering the number of patients who required occasional and/or continuous opioid administration (IV or oral opioids every 4 h for at least 24 h) in the postoperative period (Table 4).
The two most common operations performed on the lower extremities were anterior cruciate ligament reconstruction (n = 108) and knee arthroscopies for meniscal repair, knee chondroplasty and lateral retinacular release (n = 128). The addition of clonidine to the local anesthetic significantly increased the duration of sensory block after both operations (Table 5). We also examined the difference in sensory block after upper extremity operations (n = 34), which included open reduction external fixation of radial, ulnar, humerus, and elbow fractures. These patients underwent an infraclavicular nerve block performed with either ropivacaine 0.15% or bupivacaine 0.125%. Sixteen patients received local anesthetic only, and in 18 patients clonidine was added to the local anesthetic. The addition of clonidine significantly extended the duration of sensory block to 16 ± 4 from 11 ± 4 h (P = 0.0005) (Table 5).
These findings were confirmed by a more limited analysis focused only on patients who were admitted to the hospital for at least 24 h (n = 281) and were examined by a physician. Local anesthetic alone was used in 126 patients and a combination of local anesthetic and clonidine in 155 patients. The duration of sensory block was significantly longer for patients who received clonidine (17.1 ± 5 h) compared with that of patients who did not receive clonidine (13.1 ± 5) (P = 0.0001).
A regression analysis, which analyzed the relationship between duration of sensory block and age, sex, type of peripheral nerve block, use of clonidine, physician who performed the block, type of local anesthetic, and concentration showed a slight linear relationship between duration of sensory block and administration of clonidine (r2 = 0.25, P = 0.001). The multivariate regression analysis confirmed that clonidine was the only predictor of prolonged sensory blockade (P = 0.034). This finding was confirmed by stepwise regression, which considered the same variables previously analyzed (P = 0.005).
The overall incidence of motor block was 12%. Motor block duration was on average 8 ± 5 h. Patients who received clonidine were more likely to experience a motor block (19% vs 6%, P = 0.001). Motor block duration was significantly longer when clonidine was added to the local anesthetic (9.6 ± 5 vs 4.3 ± 4 h, P = 0.014). No correlation was found between the concentration of local anesthetic used and the incidence of motor block. The incidence of motor block was significantly more frequent after sciatic nerve blocks (29%) and infraclavicular nerve blocks (24%) compared with the other blocks considered in the analysis where the incidence ranged between 0% (fascia iliaca) and 10% (lumbar plexus) (P = 0.001). A stepwise regression confirmed that the use of clonidine (P = 0.001) followed by the type of block (P = 0.01) were the strongest predictors of motor blocks. The logistic regression (Table 6) confirmed that patients who receive clonidine and a sciatic nerve block are more likely to experience a motor block than patients who receive local anesthetic only and any other type of peripheral nerve block (risk ratio 0.87–0.91 respectively). The presence of a motor block delayed hospital discharge of patients who were scheduled for day-surgery procedures by 5.7 ± 2.5 h.
Three patients experienced prolonged numbness after peripheral nerve block. Two of them were in the LAC and one in the LA group. The numbness lasted 26 h after a sciatic nerve block, 28 h after an infraclavicular block and 72 h after a sciatic nerve block. No episodes of paresthesia or dysesthesia were observed.
This study shows that the addition of clonidine to bupivacaine or ropivacaine can extend the duration of peripheral nerve blocks in children. The effects of clonidine are independent from the type of local anesthetic used and operation performed. We did not see any effect of clonidine when higher concentrations of bupivacaine or ropivacaine were used. Although this observation seems to confirm previous reports (9,10), the study was not powered to detect a difference.
The use of clonidine in peripheral nerve blocks in adults is controversial. Most of the published reports have described the effects of clonidine on upper extremity nerve blocks. Approximately 30% of these studies have failed to show any effect of clonidine, independently from the type of local anesthetic used (ropivacaine, bupivacaine, and mepivacaine) (7–9). Similar contradictory results have been reported in the few studies conducted on lower extremities (10,11). An accurate analysis of these studies can explain these discrepancies. In some studies, the number of patients enrolled was too small to detect any effect of clonidine (11). In others, patients were not followed long enough (12 h), before any effect of clonidine could be detected (9). In another study, the authors found (surprisingly) that the time to first administration of opioids after the nerve block was shorter in patients who received local anesthetic and clonidine, compared with those who received local anesthetic only (7). Several authors have also questioned the validity of studies showing enhancement of sensory block by clonidine because they were conducted on patients undergoing only mildly painful operations (4,6,12–14) or because clonidine was combined with short-acting local anesthetics such as lidocaine (13,15) and mepivacaine (16).
Our data suggest that the addition of clonidine to a local anesthetic can extend the duration of the sensory and motor block in children.
In this report, we analyzed the effects of clonidine on a wide range of patients who had undergone painful procedures, such as anterior cruciate ligament reconstruction and open reduction internal fixation of the elbow. We also combined clonidine with long-acting local anesthetics, such as bupivacaine and ropivacaine. Clonidine appeared to significantly extend the duration of sensory block and analgesia, even when data were corrected for type of local anesthetic used, and type of block and operation performed.
Being a retrospective review, this report has obvious limitations. These limitations include potential anesthesiologist bias toward choice of medications when performing the nerve blocks and nurse and physician bias when evaluating patients in the postoperative period. However, we found a similar trend between duration of analgesia and duration of sensory block. The duration of analgesia was determined by patients’ need for rescue IV or oral opioids, and was based on patients reporting new onset of pain. This variable was not dependent on medical personnel evaluation. The likelihood of physician bias was also minimized by the fact that 11 different physicians performed the peripheral nerve blocks in the study period. Technical factors related to physician skills may influence the immediate success rate of peripheral nerve block and should have no effect on the duration of the block itself. Another possible limitation is that the follow-up was done by telephone for 32% of the patients. However, we found that clonidine significantly prolongs the duration of the sensory block, even when we excluded these patients from analysis and considered only data obtained from patients who were hospitalized after the operation.
Given these limitations, we believe that a retrospective study, when data are accurately collected and are sufficiently comprehensive, can offer important information. The large scale of this report has allowed us to address some of the potential problems that emerged from previous studies, which offered contradictory results on the effect of clonidine. We analyzed 415 patients and multiple variables in our statistical analysis. In particular, we considered factors well known for having an effect on the duration of sensory block and analgesia, such as different concentrations of two local anesthetics, several surgical procedures of different complexity, and different types of peripheral nerve blocks.
The addition of clonidine to local anesthetic significantly increased the incidence of motor blockade, and this had an effect on the hospital discharge after day-surgery procedures because it was impossible to have a satisfactory neurologic examination until the resolution of motor block. We used a low concentration of local anesthetic in our patients, as our objective in these young patients was to achieve postoperative analgesia rather than surgical anesthesia. The relatively higher incidence of motor blockade after clonidine, independent from the concentration of local anesthetic used, should be considered, particularly in those surgical procedures where a complete neurological evaluation is needed in the immediate postoperative period.
There are two main theories on how clonidine may prolong sensory anesthesia (17). One of these suggests that clonidine may produce local vasoconstriction, resulting in a delayed absorption of local anesthetic and block prolongation (18,19) The second is that clonidine may directly bind to α2-adrenergic receptors to modify neuronal excitability (20) rather than acting centrally on the locus coeruleus (21). Our data seem to confirm the local effect of clonidine because of the higher incidence and longer duration of motor blocks observed in patients who received it, as suggested in a previous report (6).
Our study participants did not experience any side effects from clonidine in the peripheral nerve blocks other than prolonged motor blockade. Although no data are available in the literature on the safety of using clonidine for peripheral nerve blocks, there are multiple data on the side effects caused by epidural (22) and intrathecal clonidine (23). These include hypotension and sedation, which seem to be dose-dependent and significantly increased by doses equal to or more than 2 μg/kg (24,25).
The results from this study question the clinical advantages of adding clonidine to local anesthetics for peripheral nerve blocks. A 4–5-h increase in the duration of a sensory block may not provide a significant improvement in the quality of patients’ postoperative course, particularly when facing a higher risk of developing motor blockade. The possibility of worsening pain during the night, after children have been discharged home, should also been considered by physicians caring for these patients. However, prolonged block may be of greatest benefit to the youngest patients by allowing a longer pain-free period. Also, the prolongation of sensory block may help to get a child through the night, depending on the timing of block administration.
We conclude that the addition of clonidine to low concentrations of ropivacaine or bupivacaine can extend the duration of sensory block and analgesia time in children. The clinical relevance of this prolonged sensory blockade, though useful in certain situations, may be limited overall, when considering the higher incidence of motor blockade caused by clonidine.
1. Ansermino M, Basu R, Vandebeek C, Montgomery C. Nonopioid additives to local anaesthetics for caudal blockade in children: a systematic review. Paediatr Anaesth 2003;13:561–73.
2. Constant I, Gall O, Gouyet L, et al. Addition of clonidine or fentanyl to local anaesthetics prolongs the duration of surgical analgesia after single shot caudal block in children. Br J Anaesth 1998;80:294–8.
3. Rochette A, Raux O, Troncin R, et al. Clonidine prolongs spinal anesthesia in newborns: a prospective dose-ranging study. Anesth Analg 2004;98:56–9.
4. Casati A, Magistris L, Beccaria P, Cappelleri G, Aldegheri G, Fanelli G. Improving postoperative analgesia after axillary brachial plexus anesthesia with 0.75% ropivacaine. A double-blind evaluation of adding clonidine. Minerva Anestesiol 2001;67:407–12.
5. 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.
6. Iskandar H, Guillaume E, Dixmerias F, et al. The enhancement of sensory blockade by clonidine selectively added to mepivacaine after midhumeral block. Anesth Analg 2001;93:771–5.
7. 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.
8. Duma A, Urbanek B, Sitzwohl C, et al. Clonidine as an adjuvant to local anaesthetic axillary brachial plexus block: a randomized, controlled study. Br J Anaesth 2005;94:112–16.
9. Erlacher W, Schuschnig C, Orlicek F, et al. The effects of clonidine on ropivacaine 0.75% in axillary perivascular brachial plexus block. Acta Anaesthesiol Scand 2000;44:53–7.
10. Couture DJ, Cuniff HM, Maye JP, Pellegrini J. The addition of clonidine to bupivacaine in combined femoral-sciatic nerve block for anterior cruciate ligament reconstruction. AANA J 2004;72:273–8.
11. Mannion S, Hayes I, Loughnane F, et al. Intravenous but not perineural clonidine prolongs postoperative analgesia after psoas compartment block with 0.5% levobupivacaine for hip fracture surgery. Anesth Analg 2005;100:873–8.
12. Casati A, Magistris L, Fanelli G, et al. Small-dose clonidine prolongs postoperative analgesia after sciatic-femoral nerve block with 0.75% ropivacaine for foot surgery. Anesth Analg 2000;91:388–92.
13. Adnan T, Elif AA, Ayse K, Gulnaz A. Clonidine as an adjuvant for lidocaine in axillary brachial plexus block in patients with chronic renal failure. Acta Anaesthesiol Scand 2005;49:563–8.
14. El Saied AH, Steyn MP, Ansermino JM. Clonidine prolongs the effect of ropivacaine for axillary brachial plexus blockade. Can J Anaesth 2000;47:962–7.
15. Bernard JM, Macaire P. Dose-range effects of clonidine added to lidocaine for brachial plexus block. Anesthesiology 1997;87: 277–84.
16. Singelyn FJ, Dangoisse M, Bartholomee S, Gouverneur JM. Adding clonidine to mepivacaine prolongs the duration of anesthesia and analgesia after axillary brachial plexus block. Reg Anesth 1992;17:148–50.
17. Buckenmaier CC III, Bleckner LL. Anaesthetic agents for advanced regional anaesthesia: a North American perspective. Drugs 2005;65:745–59.
18. Masuki S, Dinenno FA, Joyner MJ, Eisenach JH. Selective α2-adrenergic properties of dexmedetomidine over clonidine in the human forearm. J Appl Physiol 2005;99:587–92.
19. Neal JM. Effects of epinephrine in local anesthetics on the central and peripheral nervous systems: neurotoxicity and neural blood flow. Reg Anesth Pain Med 2003;28:124–34.
20. Butterworth JF, Strichartz GR. The α2-adrenergic agonists clonidine and guanfacine produce tonic and phasic block of conduction in rat sciatic nerve fibers. Anesth Analg 1993;76:295–301.
21. Eisenach JC, De Kock M, Klimscha W. α(2)-Adrenergic agonists for regional anesthesia. A clinical review of clonidine (1984– 1995). Anesthesiology 1996;85:655–74.
22. Narchi P, Benhamou D, Hamza J, Bouaziz H. Ventilatory effects of epidural clonidine during the first 3 hours after caesarean section. Acta Anaesthesiol Scand 1992;36:791–5.
23. Rochette A, Troncin R, Raux O, et al. Clonidine added to bupivacaine in neonatal spinal anesthesia: a prospective comparison in 124 preterm and term infants. Paediatr Anaesth 2005;15:1072–7.
24. Klimscha W, Chiari A, Michalek-Sauberer A, et al. The efficacy and safety of a clonidine/bupivacaine combination in caudal blockade for pediatric hernia repair. Anesth Analg 1998;86:54–61.
25. Sharpe P, Klein JR, Thompson JP, et al. Analgesia for circumcision in a paediatric population: comparison of caudal bupivacaine alone with bupivacaine plus two doses of clonidine. Paediatr Anaesth 2001;11:695–700.