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Anesth Analg 2004;99:1231-1238
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000133580.54026.65

REGIONAL ANESTHESIA

Small-Dose Intrathecal Clonidine and Isobaric Bupivacaine for Orthopedic Surgery: A Dose-Response Study

Stephan Strebel, MD*, Jürg A. Gurzeler, MD{dagger}, Markus C. Schneider, MD*, Armin Aeschbach, MD*, and Christoph H. Kindler, MD*

*Department of Anesthesia, University Clinics, Kantonsspital, Basel; and {dagger}Department of Surgery, Kantonsspital Luzern, Luzern, Switzerland

Address correspondence and reprint requests to Christoph H. Kindler, MD, Department of Anesthesia, University Clinics Basel, Kantonsspital, CH-4031 Basel, Switzerland. Address e-mail to ckindler{at}uhbs.ch


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We examined the dose-response relationship of intrathecal clonidine at small doses (≤150 µg) with respect to prolonging bupivacaine spinal anesthesia. We aimed for establishing doses of intrathecal clonidine that would produce clinically relevant prolongation of spinal anesthesia and pain relief without significant side effects. Eighty orthopedic patients were randomly assigned to intrathecally receive isobaric 0.5% bupivacaine, 18 mg, plus saline (Group 1), clonidine 37.5 µg (Group 2), clonidine 75 µg (Group 3), and clonidine 150 µg (Group 4). Duration of the sensory block (regression below level L1) was increased in patients receiving intrathecal clonidine: 288 ± 62 min (Group 1, control), 311 ± 101 min in Group 2 (+8%), 325 ± 69 min in Group 3 (+13%), and 337 ± 78 min in Group 4 (+17%) (estimated parameter for dose 0.23 [95% confidence interval –0.05–0.50]). Duration of pain relief from intrathecal clonidine administration until the first request for supplemental analgesia was significantly prolonged: 295 ± 80 min (Group 1, control), 343 ± 75 min in Group 2 (+16%), 381 ± 117 min in Group 3 (+29%), and 445 ± 136 min in Group 4 (+51%) (estimated parameter for dose 1.02 [95% confidence interval 0.59–1.45]). Relative hemodynamic stability was maintained and there were no between-group differences in the sedation score. We conclude that small doses of intrathecal clonidine (≤150 µg) significantly prolong the anesthetic and analgesic effects of bupivacaine in a dose-dependent manner and that 150 µg of clonidine seems to be the preferred dose, in terms of effect versus unwarranted side effects, when prolongation of spinal anesthesia is desired.

IMPLICATIONS: Small doses of intrathecal clonidine (≤150 µg) coadministered to isobaric bupivacaine provide dose-dependent and clinically significant prolongation of spinal anesthesia and pain relief while preserving hemodynamic stability and causing no sedation. In contrast to other approaches to prolong spinal anesthesia (combined spinal-epidural technique) or to relieve postoperative pain (intrathecal opioids), intrathecal clonidine ≤150 µg does not cause an additional technical challenge or unpredictable pharmacological risk.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Clonidine prolongs the duration of intrathecally administered local anesthetics and has potent antinociceptive properties (1–6). Although such prolongation of the effects of local anesthetics has been reported for oral (6,7) and IV (8) clonidine administration, the intrathecal route is more effective in prolonging bupivacaine spinal anesthesia (4,9). Whereas a recent report established 1–2 µg/kg intrathecal clonidine as an adequate dose for prolonging plain bupivacaine spinal anesthesia in newborns (10), the optimal dose in adults in terms of effects versus side effects of intrathecal clonidine by itself is controversial (11–13). The commonly used doses in the range of 150–300 µg were arbitrarily chosen; a real dose-response study for intrathecal clonidine has not been performed in humans. In animals, the relationship between clonidine added to spinal tetracaine and the duration of both sensory and motor blockade reached a plateau at 150 µg of clonidine (14). In humans, a marked decrease in arterial blood pressure (BP) was observed with 75 µg of intrathecal clonidine (in combination with intrathecal morphine) (11), whereas relative hemodynamic stability was maintained with doses ≥150 µg, as demonstrated by using clonidine as a sole analgesic (13). However, in the dose range of 150–450 µg, clonidine causes marked sedation (13). Because of this clinically relevant side effect, there is a tendency toward the use of smaller doses (<150 µg). Such doses of clonidine producing only minimal side effects would be a true alternative to other technical or pharmacological procedures aimed at prolonging spinal anesthesia and analgesia, such as combined spinal epidural anesthesia or intrathecal opioids, which both have adverse effects or risks. Clinical research using clonidine in the dose range of 15–75 µg, however, has focused primarily on labor analgesia (15–19) and there are only a few clinical studies testing such doses, often in combination with intrathecal opioids, in surgical procedures (20–23). In the present study, therefore, we investigated the effects of clonidine alone in the range of 37.5–150 µg, added to 0.5% intrathecal isobaric bupivacaine, in orthopedic patients scheduled for hip or knee arthroplasties. We hypothesized that intrathecal clonidine ≤150 µg prolongs spinal anesthesia and analgesia. The primary outcomes studied were time to regression of spinal blockade below level L1 and duration of pain relief, defined as the time from intrathecal clonidine administration to first request for supplemental analgesia by patients. Postoperative cumulative morphine consumption, visual analog scale (VAS) pain scores, motor blockade, hemodynamic variables, use of IV ephedrine, additional fluid requirements, and sedation were also recorded.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After approval from the local ethical committee and written informed consent, 80 ASA physical status I–III patients scheduled for elective hip or knee arthroplasties were enrolled in the study. Patients using {alpha}-adrenergic receptor antagonists, calcium channel blockers, angiotensin-converting enzyme inhibitors, showing dysrhythmias in the electrocardiogram, and patients who had a history of low-back surgery, a body weight >120 kg, or height <150 cm were excluded from the study. Using a computer-generated random list, the patients were divided into 4 groups of 20 individuals. All patients received a coded intrathecal drug volume of 4.6 mL. The dose of isobaric 0.5% bupivacaine, 18 mg, was identical in all study groups. The active study groups (Groups 2–4) received clonidine (Catapressan®; Boehringer Ingelheim, Germany), 37.5 µg (Group 2), 75 µg (Group 3), or 150 µg (Group 4) added to bupivacaine in the same syringe; the control group (Group 1) received an identical volume of saline added to bupivacaine.

Before surgery, all patients were given instructions on how to use patient-controlled analgesia (PCA) and the 10-point VAS to assess pain intensity. PCA was supplied by IV morphine (1 mg/mL) with a 2-mL bolus dose, a lockout period of 10 min, a 4-h maximal dose of 40 mg, and no basal infusion rate. Droperidol (0.1 mg/mL) was added to the PCA solution to reduce the incidence of postoperative nausea and vomiting.

All patients had spinal anesthesia according to a standard protocol. An oral 1.5- to 6-mg bromazepam premedication was given 2 h preoperatively. After hydration with 250 mL of Ringer’s lactate solution, a midline spinal puncture was performed at L3/4 (at L2/3 if for an anatomical reason it was not possible at L3/4) with the patient in the lateral decubitus position using a 25-gauge Quincke spinal needle (Braun, Melsungen, Germany). The L3/4 interspace was identified by a line between the upper borders of the iliac crest passing through the spinous process L4 or the interspace between L4 and L5. All injections were made at a rate of about 1 mL in 4–5 s and intrathecal solutions were at room temperature. Thereafter, the patients were placed in the supine position for surgery. A tourniquet with a maximal pressure of 350 mm Hg was applied to all patients scheduled for knee arthroplasty. During surgery, Ringer’s lactate solution was infused at a rate of 150 mL/h. Additional IV fluids (crystalloids, colloids, and blood) were administered as perioperatively dictated by blood loss and hemodynamic instability. Blood loss >500 mL was replaced with maximally 1000 mL of hetastarch or by packed red cells if hemoglobin was <90 g/L. Hemodynamic instability was defined as a 30% reduction in mean arterial BP from baseline value and was treated with 300 mL of additional fluids or, if not responsive within 5 min, with IV ephedrine (5-mg bolus). If, intraoperatively, a need for additional sedation was expressed, IV midazolam was given intermittently (1-mg bolus).

Baseline observations were started before intrathecal drug injection. Heart rate, electrocardiogram, noninvasive arterial BP, and peripheral oxygen saturation were monitored intraoperatively. After intrathecal drug injection, data recording was performed during the first hour at 15, 30, 45, and 60 min, and thereafter every hour up to 8 h, followed by 4-h intervals up to 24 h. The cephalad extension of anesthesia was assessed on both sides of the body using temperature discrimination at each dermatomal level, i.e., the sensation of cold elicited by ether swabs in the midclavicular line. When levels of anesthesia were not equal bilaterally, the higher level was used for statistical purposes. To evaluate the extension of the sensory block, the number of dermatomal segments above the lumbar injection site was assessed. All determinations of the sensory levels were based on a dermatomal chart (ASTRA; Astra Pharmaceutica AG Zürich, Switzerland). Duration of anesthesia was measured as the time interval from intrathecal injection to regression of the sensory block below L1.

The intensity of pain was assessed using a 10-point VAS. Duration of pain relief was defined as the time from intrathecal clonidine administration to the first request for supplemental analgesia by PCA. In addition, required and total delivered PCA demands and boluses of morphine were recorded. Lower limb motor blockade was graded according to the Bromage scale (24). Sedation was scored on a 5-point scale ranging from 0 to 5 (0 = fully awake, alert to 5 = deeply asleep, not responding to verbal commands). All data collection was performed by persons not involved in patient care. Complete recovery from the clonidine-induced prolonged sensory and motor block was documented in all patients.

The sample size of 20 patients per group was based on the assumption that an increase of 60 min in the duration of spinal anesthesia and an increase of 30% in the time interval from spinal anesthesia to the first request for supplemental analgesia would be detected ({alpha} = 0.05; ß = 0.8), both of which were considered clinically meaningful. Unless stated otherwise, data are expressed as mean ± SD. The comparison of normally distributed continuous variables among the groups was performed by means of one-way analysis of variance, and, if appropriate, with Bonferroni correction. For comparison of only two groups, the Student’s t-test was used. Ranked data among the groups were compared using the Kruskal-Wallis test. Nominal categorical data among the groups were compared using either {chi}2 analysis or Fisher’s exact test. To estimate the effect of clonidine dose on the duration of sensory block and pain relief, a multivariate regression model using patients’ age, weight, and height as covariates was used (SAS version 8.2; SAS Institute Inc., Cary, NC). The proportion of patients requiring no additional analgesia was analyzed by the Kaplan-Meier method followed by the log-rank test. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Of the 80 patients enrolled in the study, 75 completed the study protocol and were included in the data analysis. Thus, the final Group 1 consisted of 20, Group 2 of 17, Group 3 of 18, and Group 4 of 20 patients. The treatment groups did not differ significantly with respect to any of the demographic variables or scheduled surgery (hip versus knee arthroplasty) (Table 1). Neither baseline pain and sedation scores nor physiological data differed significantly among the four groups.


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  		Table 1. Demographic Data
 
The duration of sensory block was prolonged by the addition of intrathecal clonidine in a dose-dependent manner. Time to regression of spinal anesthesia below level L1 was 288 ± 62 min in Group 1 (control), 311 ± 101 min (+8%) in Group 2, 325 ± 69 min (+13%) in Group 3, and 337 ± 78 min (+17%) in Group 4 (estimated parameter for dose 0.23 [95% confidence interval, CI, –0.05–0.50]). The time interval between spinal anesthesia and the first request for supplemental PCA morphine was significantly longer in all clonidine groups: 295 ± 80 min in Group 1 (control), 343 ± 75 min (+16%) in Group 2, 381 ± 117 min (+29%) in Group 3, and 445 ± 136 min (+51%) in Group 4 (estimated parameter for dose 1.02 [95% CI 0.59–1.45]) (Fig. 1). In addition, the VAS scores were significantly reduced in Group 4 compared with Group 1 at 6, 7, and 8 h (Fig. 2). However, there was no difference in either required PCA demands (51 ± 13 for Group 1, 29 ± 7 for Group 2, 29 ± 6 for Group 3, and 34 ± 10 for Group 4) or in total delivered PCA boluses during the first 24 h (43 ± 5 for Group 1, 29 ± 7 for Group 2, 27 ± 4 for Group 3, and 32 ± 5 for Group 4; mean ± SE).


Figure 1
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  		Figure 1. Log-rank curves for duration of pain relief. The curves represent the proportion of patients who had not yet received additional analgesics after the intrathecal injection of 18 mg of 0.5% bupivacaine plus saline (Group 1), 18 mg of 0.5% bupivacaine plus 37.5 µg of clonidine (Group 2), 18 mg of 0.5% bupivacaine plus 75 µg of clonidine (Group 3), and 18 mg of 0.5% bupivacaine plus 150 µg of clonidine (Group 4). P < 0.0001 between groups (log-rank test). PCA = patient-controlled analgesia.

 

Figure 2
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  		Figure 2. Visual analog scale (VAS). VAS pain scores are shown during 16 h after spinal anesthesia for Group 1 (18 mg of 0.5% bupivacaine plus saline), Group 2 (18 mg of 0.5% bupivacaine plus 37.5 µg of clonidine), Group 3 (18 mg of 0.5% bupivacaine plus 75 µg of clonidine), and Group 4 (18 mg of 0.5% bupivacaine plus 150 µg of clonidine). *Significant differences among Group 4 compared with Group 1 at 6, 7, and 8 h after spinal anesthesia (P < 0.05; analysis of variance, Bonferroni post hoc test).

 
The range of the upper level of sensory blockade was similar in all groups: T1-T10 (Group 1), T1-L1 (Group 2), T1-T10 (Group 3), and T1-T12 (Group 4). The maximal extension of the sensory blockade (number of dermatomes above the lumbar injection site) was 6 (5–7) (median, 95% CI), 4 (4–7), 5 (4–7), and 8 (6–8), respectively, indicating no statistically significant difference. A complete motor blockade of the lower extremities was observed in all patients. After 4, 5, 6, and 7 h, the Bromage grade was significantly higher in Group 4 compared with Group 1 (P < 0.05) (Fig. 3). Also, the percentage of patients with Bromage grade 3 motor blockade was significantly larger in Group 4 compared with Group 1 (P < 0.05) over a time period of 4–7 h (90% versus 40% at 4 h, 85% versus 20% at 5 h, 60% versus 5% at 6 h, and 25% versus 0% at 7 h).


Figure 3
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  		Figure 3. Motor blockade (Bromage scale) is shown for Group 1 (18 mg 0.5% bupivacaine plus saline), Group 2 (18 mg 0.5% bupivacaine plus 37.5 µg clonidine), Group 3 (18 mg 0.5% bupivacaine plus 75 µg clonidine), and Group 4 (18 mg 0.5% bupivacaine plus 150 µg clonidine). Results are expressed as mean grade. *Significant differences among Groups 1 and 4 at 4, 5, 6, and 7 h (P < 0.05; Kruskal-Wallis test).

 
There were no intergroup differences in the number of patients with a mean arterial BP decrease ≥30% (2/20, 1/17, 0/18, and 1/20) or in the maximal decrease of mean arterial BP (21% ± 13%, 25% ± 14%, 26% ± 12%, and 25% ± 13%). A small but statistically significant decrease in diastolic BP was observed in Group 2 (0.5 h, 2 h, 3 h, and 4 h), in Group 3 (1 h, 2 h, and 3 h), and in Group 4 (3 h and 6 h) (Table 2). In addition, systolic BP was decreased in Group 3 (2 h and 3 h) and in Group 4 (3 h). Cumulative fluid requirements were similar in all groups. Total IV ephedrine administration was also not statistically different among the groups (Fig. 4).


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  		Table 2. Hemodynamic Data: Arterial Blood Pressure (BP) and Heart Rate (HR)
 

Figure 4
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  		Figure 4. Intraoperative fluids and ephedrine requirements. Estimated blood loss, transfusion of blood, crystalloids, and colloids, and administration of IV ephedrine are shown for Group 1 (18 mg of 0.5% bupivacaine plus saline), Group 2 (18 mg of 0.5% bupivacaine plus 37.5 µg of clonidine), Group 3 (18 mg of 0.5% bupivacaine plus 75 µg of clonidine), and Group 4 (18 mg of 0.5% bupivacaine plus 150 µg of clonidine). P > 0.05 between groups (analysis of variance).

 
There were no significant differences in sedation scores (data not shown) or in the intraoperative use of midazolam (3.5 ± 0.4 mg, 2.1 ± 0.6, 2.9 ± 0.5 mg, and 2.6 ± 0.4 mg; mean ± SE).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Our results show a dose-dependent prolongation of both the sensory blockade of spinal anesthesia and the pain-free interval until the first request for supplemental analgesia by intrathecal clonidine in the range of 37.5–150 µg. In addition, more patients receiving 150 µg of intrathecal clonidine showed a prolonged motor blockade, potentially allowing longer orthopedic procedures such as one-stage bilateral arthroplasties or complex prothesis replacements. Relative hemodynamic stability was maintained in all groups. Interestingly, patients receiving the largest dose of intrathecal clonidine (150 µg) showed the smallest variations in hemodynamic variables. No clinically relevant between-group differences in sedation were noticed. In elderly orthopedic patients undergoing lower extremity arthroplasties, alternative anesthetic techniques to prolong spinal anesthesia, such as epidural or combined spinal epidural techniques, may be technically difficult and time consuming; in addition, the motor blockade during epidural anesthesia is often not as satisfactory for the orthopedic surgeon as during spinal anesthesia.

Numerous studies in orthopedic patients have investigated the effects of intrathecal clonidine coadministered with local anesthetics (1–3,25). However, substantial differences in the study designs make it difficult to evaluate conflicting results. Intrathecal clonidine has been used in a wide dose range of 15–400 µg, has been administered either alone or in combination with different local anesthetics or opioids, and its anesthetic and analgesic effects have been quantified and qualified in numerous ways. Until recently, only a few studies have focused on small doses of intrathecal clonidine in surgical patients (20–22).

Clonidine prolongs spinal anesthesia (1–3,13,25). Our results are in agreement with these previous studies; however, whereas these investigations used clonidine at doses up to 450 µg, our study focused on smaller doses (≤150 µg). The use of such doses has shown favorable results for labor analgesia in terms of prolonging analgesia (16,26). In these trials, however, clonidine was combined with different opioids. Experimental studies have shown that both opioids and {alpha}2-adrenergic receptor agonists administered intrathecally are able to relieve visceral pain (27). In addition, many reports have shown an interaction for opioids and {alpha}2-adrenergic receptor agonists that is either synergistic or additive (27,28). Furthermore, pregnancy-induced physiological changes associated with high levels of endorphins may be responsible for the beneficial effect of clonidine for labor analgesia (29). Outside of obstetric anesthesia, only a few investigators used intrathecal clonidine at doses <150 µg. Clonidine 15–30 µg significantly prolonged sensory blockade of spinal anesthesia or improved postoperative analgesia for gynecological surgery (22), knee arthroscopy (20), and ambulatory inguinal herniorrhaphy (21).

The antinociceptive properties of clonidine indicate that it might be useful as an alternative to intrathecal opioids for postoperative analgesia (5). A dose-dependent analgesic effect has been observed after intrathecal clonidine alone, i.e., without local anesthetics, after elective cesarean delivery (13,30). The use of clonidine for postoperative analgesia coadministered with local anesthetics has also been previously described (1,3,22). In our study, clonidine significantly increased in a dose-dependent manner the interval from spinal anesthesia to the first request for supplemental PCA morphine. We also found significantly reduced VAS pain scores in patients receiving 150 µg of clonidine, but not smaller doses, which is in agreement with previous trials (3,30). However, in contrast to other reports, we found no difference in total morphine consumption or in PCA demands (3,11).

Significantly prolonged motor blockade after intrathecal clonidine has been reported with doses ≥75 µg (1,2,25). We also observed a significantly larger proportion of patients with intense motor blockade that resolved after 8–10 hours in patients who received 150 µg intrathecal clonidine compared with control patients. Sedation, a central effect of {alpha}2-adrenergic drugs, occurs after systemic, epidural, or intrathecal administration of clonidine in humans (28,30). Marked changes in sedation were observed in patients receiving 3 µg/kg intrathecal clonidine (1). Other studies reported increased sedation with 150 µg and larger doses of intrathecal clonidine as the sole analgesic for pain relief (13,30). In contrast, sedation was not significantly different among patients of our study who received no more than 150 µg of clonidine.

We observed a small arterial BP reduction by clonidine in the tested dose range. These findings agree with other investigations demonstrating a decrease in arterial BP with such doses and relative hemodynamic stability with administration of larger doses. In orthopedic patients, no significant changes in hemodynamic variables were observed with 150 µg (2), relative cardiovascular stability was reported for 75–100 µg (3), and a significant decrease of mean arterial BP was found for 75 µg of intrathecal clonidine (albeit in combination with 0.5 mg of intrathecal morphine) (11). Clonidine, after neuraxial or systemic administration, affects arterial BP in a complex manner because of opposing actions at multiple sites. The {alpha}2-adrenergic agonists produce sympathicolysis and reduce arterial BP through effects at specific brainstem nuclei and on sympathetic preganglionic neurons in the spinal cord, effects that are counteracted by direct vasoconstriction resulting from the {alpha}2-adrenergic agonists on the peripheral vasculature. As a result, the dose response for neuraxial clonidine on arterial BP in humans is generally considered to be U-shaped (28,29). The rather complex action of intrathecally injected {alpha}2-adrenergic receptor agonists on hemodynamic variables further depends on the segmental site of injection, the patient’s position, the rate of injection, and the temperature of the injected solution. In an attempt to minimize the influence of these factors on patients’ hemodynamics, we followed a strict protocol for spinal anesthesia. Furthermore, combining {alpha}2-adrenergic receptor agonists with local anesthetics can potentially increase the degree of sympathicolysis and resulting hypotension. However, clinical studies in surgical patients on this matter have only infrequently reported increased reductions in arterial BP or heart rate in patients who received both intrathecal clonidine and local anesthetics (28). In contrast, in obstetric analgesia, a wide dose range of 15–200 µg of intrathecal clonidine demonstrated a substantial production of hypotensive effects (12,15,17,19,26). This might be the result of a combined effect of intrathecal clonidine and opioids (11). Alternatively, parturients might be particularly sensitive to intrathecal clonidine. The increased hypotension observed with larger clonidine doses might also be attributed to its rostral spread to thoracic levels and to the brainstem. Because clonidine becomes slightly hypobaric at body temperature, rostral spread might have occurred with the parturient in the sitting position for several minutes after the intrathecal injection (31).

A potential limitation of our study design was setting the upper limit of the tested dose range at 150 µg of clonidine. Therefore, we cannot exclude the possibility that larger clonidine doses, in the range between >150 and <300 µg, might have demonstrated an even better effect versus side effect profile. Another limitation relates to the sample size; the study was underpowered to detect potentially significant differences in secondary outcome variables such as sedation, arterial BP, and heart rate. However, a post hoc analysis of our data confirmed enough power to detect clinically relevant differences for these variables.

In summary, the addition of intrathecal clonidine at doses ≤150 µg to isobaric bupivacaine dose-dependently prolongs both sensory blockade of spinal anesthesia and time interval to first request for supplemental analgesia. Because of the absence of significant adverse effects, we conclude that, within the tested dose range, 150 µg of clonidine is the preferred dose, in terms of effect versus side effects, when prolongation of spinal anesthesia is desired as, for example in patients scheduled for long, lower extremity orthopedic procedures.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication May 5, 2004.





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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press