The α2-adrenergic agonist, clonidine, has been increasingly used in combination with epidural or spinal anesthesia (1) because of the augmentative properties of the α 2-adrenergic agonists during concomitant administration of analgesics (2). The prolonged analgesic effect of clonidine is generally recognized to be an α2-adrenoceptor stimulation in the spinal cord (1). However, the prolonged effect might be attributable in part to local vasoconstriction, such as that of epinephrine in the epidural space, thereby reducing the vascular removal of local anesthetic surrounding neural structures. Moreover, the effect of clonidine on the reabsorption of local anesthetics into the systemic circulation from the epidural space has not been fully elucidated. Although several reports have described clinical (3,4) or animal (5) observations with the purpose of evaluating plasma local anesthetic concentrations during epidural anesthesia, the number of published observations remains limited and they show contradictory results (3–5).
Continuous epidural anesthesia has been increasingly used for anesthesia and analgesia during and after surgery in children, but there is no report concerning lidocaine pharmacokinetics during anesthesia in children receiving oral clonidine premedication. Therefore, we performed this study to assess concentrations of plasma lidocaine and its major metabolite (monoethylglycinexylidide [MEGX]) in children receiving continuous thoracic epidural anesthesia after oral clonidine preanesthetic medication.
We studied 10 male pediatric patients, ASA physical status I, ranging in age from 1–9 yr, who were scheduled for general anesthesia combined with continuous thoracic epidural anesthesia for elective cystourethroplasty. The study protocol was approved by the Clinical Investigation Committee of the University of Tsukuba, and informed consent was obtained from the parent or guardian of each patient. Preoperative examination disclosed no hepatic, renal, or metabolic dysfunction in any patient. In addition, any patient who had ingested drugs such as antihistamines, depressants, or antiseizure medication was excluded from the study.
All patients were fasted for a minimum of 5 h before induction of anesthesia. Venous access was obtained for infusion of lactated Ringer’s solution at a rate of 6 mL · kg−1 · h−1 before entrance into the operating room. A precordial stethoscope was used to monitor heart and breath sounds in the operating room. The patients were monitored with an electrocardiograph, a pulse oximeter, and an AS/3™ (Datex, Helsinki, Finland) to measure blood pressure indirectly. Throughout the study the inspired and end-tidal anesthetic concentrations were measured with a gas monitor (AS/3™), which was calibrated before each use.
Ten pediatric patients were randomly allocated, using computer generated numbers, to either the Control or the Clonidine group (n = 5 each). Each patient received a placebo (Control) or 4 μg/kg of oral clonidine 100 min before entering the operating room.
Anesthesia was induced and maintained with sevoflurane in oxygen and air (Fio2 40%) without IV anesthetics or neuromuscular relaxants throughout the study. Body temperature was monitored by a nasopharyngeal probe and was kept constant at 36.8 ± 0.4°C with a heating pad.
After the trachea was intubated, a radial arterial catheter was inserted for blood samplings and continuous blood pressure measurements. An epidural puncture was carefully performed with a 19-gauge, 5-cm Tuohy needle at the Th11–12 intervertebral space using a median approach in the lateral flexed position. We identified the epidural space using the pressure-guided method (6), with the pressure at the tip of the Tuohy needle monitored by a pressure transducer. As soon as the tip of the needle entered the epidural space, the pressure suddenly decreased, and the pressure tracing was synchronized with the heartbeats. A 21-gauge catheter was inserted and advanced approximately 3 cm into the epidural space. The patient was then placed supine, and an initial dose of 1% lidocaine (5 mg/kg) was injected through a catheter into the epidural space after an aspiration test was established, followed by an infusion of the same solution (2.5 mg · kg−1 · h−1) using a motor-driven syringe pump. Anesthesia was maintained with 1.5% sevoflurane in oxygen and air.
Twenty minutes after the initial dose of lidocaine, the surgical procedure was started. A successful block was defined as one in which there was no hemodynamic response to surgical stimuli during a 10-min period after incision of the lower abdominal area. A positive response was defined as a 15-mm Hg increase in systolic blood pressure or a 20-bpm increase in heart rate. The patients who showed positive responses were regarded as not having successful epidural anesthesia. They were immediately given 4%–5% sevoflurane and excluded from the study.
Blood samples were drawn at 15 min, 30 min, and every 60 min for 4 h after the initiation of continuous epidural injection. Plasma samples were separated by centrifugation at 4°C and stored at −20°C until analyzed.
Determination of Plasma Lidocaine and MEGX Concentrations
MEGX was kindly provided by Astra Japan (Osaka, Japan). We used the assay reported by Tanaka et al. (7) to determine the plasma lidocaine and MEGX concentrations. The high-pressure liquid chromatography equipment consisted of a pump (Model CCPS; Tosoh, Tokyo, Japan) and a variable-wavelength ultraviolet detector (Model UV-8000, Tosoh). Separation was achieved using a C-18 reversed-phase column (150 mm × 4.6 mm inner diameter, particle size 5 μm, TSK-gel ODS80-TM; Tosoh). The mobile phase was composed of 0.05M KH2PO4-acetonitril (86:14, v/v) (pH 4.0), and the flow rate was 0.8 mL/min. The absorbance of the eluate was monitored at 210 nm. All instruments were operated at ambient laboratory temperature (ca. 23°C). The retention times of MEGX, internal standard, and lidocaine were approximately 8.4, 10, and 13 min, respectively. With this assay method, the extraction recoveries from plasma for lidocaine and MEGX were 96.6 and 91.2% at 10 μg/mL, respectively. The maximum coefficient of variation value for within-run or between-run precision was 3.3%, and detection limits for lidocaine and MEGX were 10 ng/mL using 250 μL of plasma sample.
Patient demographic and clinical data were expressed as the mean ± se. Statistical comparisons between the two premedication groups (Control group with placebo; Clonidine group with 4 μg/kg of clonidine dose) were performed using the Mann-Whitney U-test. Statistical comparisons within each group were performed using repeated-measures analysis of variance, and significance was assessed using the Scheffe F-test. In all cases, P values <0.05 were considered the minimum level of statistical significance.
We have been performing this study for four years in children receiving continuous thoracic epidural anesthesia. However, only a small number of subjects had a sufficiently long enough period of anesthesia to allow us to perform the study. The demographic data of the patients enrolled in the study are summarized in Table 1. There was no significant difference between the two groups with respect to age, weight, gender, duration of lidocaine infusion, MAC-hours, drip infusion ratio, or blood loss. Systolic blood pressure and heart rate values also were statistically similar between the two groups during anesthesia. However, patients receiving clonidine showed lower systolic blood pressure than that of patients in the Control group at baseline values measured before the induction of anesthesia (P < 0.05) (Table 1). The placement of the epidural catheter was performed easily and successfully at the first attempt in all patients. All patients obtained a successful epidural block judged by the hemodynamic criteria against surgical stimuli. Plasma lidocaine concentration differed significantly between the groups until 240 min after the initiation of epidural infusion (P < 0.05), as shown in Figure 1. Although the concentration of MEGX tended to be smaller in the Clonidine group, it did not reach statistical significance. No patient had bradycardia or hypotension requiring treatment during the study.
This study is the first report concerning oral clonidine’s effects on epidural lidocaine in children. Although the number of subjects was small, we observed clear evidence and the results showed a significantly smaller concentration of lidocaine and a smaller plasma concentration of MEGX in children receiving oral clonidine. One possible explanation for these findings is that clonidine reduces the resorption of lidocaine into systemic circulation through epidural vessels. α2 adrenergic agonists produce clinical effects after binding to α2 adrenoceptors, of which there are three subtypes (α2a, α2b, and α2c) (8,9). The α2a adrenoceptors are located in the central nervous system (CNS) and are responsible for the blood pressure-decreasing sympatholytic effects of α2 agonists (8). The α2b adrenoceptors are located at the peripheral vascular smooth muscle and are responsible for the vasoconstrictive effects (9). Although the vasoconstrictive threshold of clonidine was 1.0 ng/mL in human digital vasculature (10), the relationship between plasma concentration of clonidine and diameter of the epidural vessels remains unknown. There is little evidence for local vasoconstriction; therefore, further studies will be needed to observe both epidural vessels and clonidine concentrations in plasma. Additionally, the large difference between lidocaine levels was observed at the 15-minute collection. These data suggest that lidocaine absorption into the vascular component is quite rapid and that the effect of clonidine is similarly rapid.
The effects of clonidine on resorption of lidocaine into systemic circulation from the epidural space have not been established in human study. Several reports have shown contradictory results in human (3,4) and animal (5) studies. First, Mazoit et al. (5) reported that epidural clonidine at a dose of 300 μg (4–6 μg/kg) decreased the maximum plasma concentration of lidocaine after an epidural bolus injection to the same extent as epinephrine (1/200,000). Another study showed that clonidine at a larger dose of 100 μg/kg IP increased the plasma concentration of lidocaine in mice (5). The larger dose of clonidine injected IP may diminish the hepatic blood flow and the hepatic metabolism of lidocaine because of its vasoconstrictive effect. Moreover, because clonidine often decreases blood pressure and/or heart rate (3), this reduction in cardiac output may be the cause of decreased hepatic blood flow, which can be ascribed to an inhibition of drug metabolism in the liver. The changes in hepatic blood flow may have caused the contradictory results in the previous studies. Both diazepam (11), administered to sedate patients during anesthesia, and lidocaine (12) were metabolized with CYP3A4, and lidocaine metabolism can be affected by diazepam. In contrast to the previous study in humans (3), we did not use diazepam in the present study, and hemodynamic variables were similar between the Control and Clonidine groups during anesthesia. These differences could also be the cause of some contradictory results.
Although the inclusion of epinephrine in local anesthetic has for many years been a clinically accepted practice to decrease the plasma concentration of local anesthetic and to prolong its analgesic effect, we previously demonstrated that the addition of epinephrine is not effective for reducing plasma lidocaine concentration during continuous epidural anesthesia (13). The concomitant use of clonidine during epidural anesthesia has recently been increasing. When given epidurally or spinally, clonidine, like epinephrine (14), was reported to have antinociceptive action (15,16) through its direct suppression of spinal cord nociceptive neurons. Moreover, clonidine easily crosses the blood-brain barrier (17), and therefore it may interact with α-adrenergic receptors at spinal and supraspinal sites within the CNS. In addition, Liu et al. (18) suggested that clonidine may affect peripheral sensory nerves as a sole drug or in combination with local anesthetics. Clonidine inhibits neurotransmission in both Aδ and C nerve fibers (19,20). In addition to the mechanisms already discussed, our data might suggest that clonidine prolongs neuronal blockade effects of local anesthetic by reducing vascular uptake, thereby maintaining a larger concentration of lidocaine surrounding the neuronal tissue for a longer period of time in epidural anesthesia.
There are some limitations to the present study. First, we could not sample blood to measure plasma clonidine concentration in children because of the current study protocol approval. Previous pharmacokinetic studies showed that the plasma concentration of clonidine increases rapidly after an oral dose and reaches a peak plasma level 1.5 hours after oral intake, with an elimination half-life of more than 10 hours (21). On the basis of these data, it is likely that clonidine concentrations in plasma were well maintained during the current study period (approximately 5 hours). Second, we did not observe the actual diameter of epidural vessels. Although epidural clonidine produces little change in spinal cord blood flow (22,23), the effect of clonidine on epidural vessels remains unknown. Thus, further studies will be needed to observe both epidural vessels and plasma clonidine concentrations.
Plasma concentration of local anesthetics administered epidurally can be affected by concomitant vasoconstrictors, the type of local anesthetic injected, the dose or volume of the drug (24) as well as the site of injection (24). Plasma concentrations of lidocaine injected at cervical or thoracic sites tended to be larger than those injected at lumbar sites (25). It is likely that the plasma concentration of lidocaine injected into only thoracic sites in this study was slightly larger than those injected at caudal, lumbar, or thoracic sites in our previous study (26). This difference may partially depend on the fact that plasma levels of local anesthetics are closely related to the vascularity of the site into which they are injected (27).
Oral clonidine premedication (dose of 4 μg/kg) reduces lidocaine concentrations in plasma by 25%–50% in children with continuous thoracic epidural anesthesia. Based on these findings, it is possible that an additional margin of safety regarding lidocaine toxicity is gained through the use of oral clonidine in children who will be placed on epidural lidocaine.
In conclusion, oral clonidine preanesthetic medication at a dose of 4 μg/kg decreases plasma lidocaine concentration in children. Our finding may have clinical implications in patients receiving continuous epidural anesthesia.
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© 2001 International Anesthesia Research Society
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