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Anesthesiology:
Clinical Investigations

Comparison of Three Solutions of Ropivacaine/Fentanyl for Postoperative Patient‐controlled Epidural Analgesia

Liu, Spencer S. MD; Moore, James M. MD; Luo, Amy M. MD; Trautman, Walter J. MD; Carpenter, Randall L. MD

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Abstract

Background: Ropivacaine, 0.2%, is a new local anesthetic approved for epidural analgesia. The addition of 4 [micro sign]g/ml fentanyl improves analgesia from epidural ropivacaine. Use of a lower concentration of ropivacaine‐fentanyl may further improve analgesia or decrease side effects.
Methods: Thirty patients undergoing lower abdominal surgery were randomized in a double‐blinded manner to receive one of three solutions: 0.2% ropivacaine‐4 [micro sign]g fentanyl, 0.1% ropivacaine‐2 [micro sign]g fentanyl, or 0.05% ropivacaine‐1 [micro sign]g fentanyl for patient‐controlled epidural analgesia after standardized combined epidural and general anesthesia. Patient‐controlled epidural analgesia settings and adjustments for the three solutions were standardized to deliver equivalent drug doses. Pain scores (rest, cough, and ambulation), side effects (nausea, pruritus, sedation, motor block, hypotension, and orthostasis), and patient‐controlled epidural analgesia consumption were measured for 48 h.
Results: All three solutions produced equivalent analgesia. Motor block was significantly more common (30 vs. 0%) and more intense with the 0.2% ropivacaine‐4 [micro sign]g fentanyl solution. Other side effects were equivalent between solutions and mild in severity. A significantly smaller volume of 0.2% ropivacaine‐4 [micro sign]g fentanyl solution was used, whereas the 0.1% ropivacaine‐2 [micro sign]g fentanyl group used a significantly greater amount of ropivacaine and fentanyl.
Conclusions: Lesser concentrations of ropivacaine and fentanyl provide comparable analgesia with less motor block despite the use of similar amounts of ropivacaine and fentanyl. This finding suggests that concentration of local anesthetic solution at low doses is a primary determinant of motor block with patient‐controlled epidural analgesia after lower abdominal surgery.
ROPIVACAINE is a new local anesthetic available as a 0.2% solution for epidural analgesia. Epidural ropivacaine appears to produce less motor block than equal doses of bupivacaine, [1] yet the use of ropivacaine alone for postoperative epidural analgesia still appears to be unsatisfactory because of motor block when administered in doses sufficient for analgesia. [2] Preliminary results from a dose‐response study adding fentanyl to ropivacaine for postoperative epidural analgesia indicate that the addition of 4 [micro sign]g/ml fentanyl improves the quality and efficacy of analgesia from 0.2% ropivacaine. [3] Although a solution of 0.2% ropivacaine and 4 [micro sign]g fentanyl may be sufficient for postoperative epidural analgesia, previous studies suggest that lower concentrations of a lipid‐soluble local anesthetic [4,5] or a lipid‐soluble opioid [6] may improve analgesia and decrease motor block. [4] However, the results from previous studies that evaluated high and low concentrations of local anesthetic combined with lipid‐soluble opioid solutions (bupivacaine and sufentanil) for postoperative epidural analgesia are conflicting, [7,8] and no information is available regarding low concentrations of ropivacaine and fentanyl for patient‐controlled epidural analgesia (PCEA). Therefore, we designed this randomized, double‐blinded study to evaluate the effects of altering concentration and volume on analgesia, motor block, and other side effects from PCEA with ropivacaine and fentanyl.
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Materials and Methods

After obtaining institutional board approval and informed consent, we randomized 30 patients undergoing elective lower abdominal surgery in a double‐blinded manner to three different solutions of ropivacaine and fentanyl for postoperative PCEA. Exclusion criteria were American Society of Anesthesiologists physical status more than III, age younger than 18 or older than 80 yr, weight less than 50 or more than 110 kg, allergy to local anesthetics or opioids, or inability to understand the use of PCEA. All patients underwent a standardized combined epidural‐general anesthetic. Patients were premedicated with intravenous midazolam (<or= to 2 mg) and fentanyl (<or= to 100 [micro sign]g). An epidural catheter was placed 3‐5 cm into the epidural space at the T12‐L2 interspace. An epidural test dose of 3 ml lidocaine, 2%, with 1:200,000 epinephrine was injected through the catheter. After a negative response to the test dose was confirmed, further lidocaine with epinephrine was titrated to a bilateral sensory block of at least dermatome T6. General anesthesia was induced with 3 to 5 mg/kg thiopental, 1 to 1.5 mg/kg succinylcholine, 3 mg curare, and 2 [micro sign]g/kg fentanyl. General anesthesia was maintained with isoflurane and oxygen. Epidural anesthesia was maintained with 33‐50% of the original dose every 60‐90 min at the discretion of the anesthesia team. Further muscle relaxation with either pancuronium or cisatracurium was administered at the discretion of the anesthesia team. Patients were awakened and their tracheas were extubated at the conclusion of surgery.
Before the surgical procedure, patients were randomized in a double‐blinded manner to receive one of three solutions of ropivacaine and fentanyl for postoperative epidural analgesia; 0.2% ropivacaine‐4 [micro sign]g/ml fentanyl, 0.1% ropivacaine‐2 [micro sign]g/ml fentanyl, or 0.05% ropivacaine‐1 [micro sign]g/ml fentanyl, which were prepared by our investigational pharmacy. Within 1 h of surgical incision, an epidural infusion of 2 ml/h 0.2% ropivacaine‐4 [micro sign]g fentanyl or 4 ml/h 0.1% ropivacaine‐2 [micro sign]g fentanyl, or 8 ml/h 0.05% ropivacaine‐1 [micro sign]g fentanyl was started. Background epidural infusions, PCEA boluses, loading doses, and adjustments in background infusion rates for inadequate analgesia were devised such that each study group received equivalent doses of ropivacaine and fentanyl (Appendix 1). If more than four adjustments in infusion rate were needed because of inadequate analgesia, the epidural catheter was tested with 5 ml lidocaine, 1%, to ensure correct placement. If the catheter was displaced, the study was discontinued. If the catheter was positioned correctly, continued adjustments were pursued. Patient monitoring and treatment of nausea, vomiting, and pruritus were standardized (Appendix 2). Motor block (inability to walk) was treated by discontinuing the background infusion for 1 h and restarting at 50% of the previous setting, if analgesia was adequate (visual analog scale [VAS] <or= to 50 of 100). In addition, the epidural catheter was withdrawn 1 cm if the motor block was unilateral. If more than two such adjustments were needed, the patient was withdrawn from the study. If analgesia was inadequate, motor block was treated by discontinuing the study. Hypotension (systolic blood pressure <90 mmHg) and orthostasis (>20% change in heart rate or systolic blood pressure from supine to upright) were initially treated with intravenous fluids (50‐1,000 ml). If hypotension or orthostasis continued and analgesia was adequate (VAS <or= to 50 of 100), then the background infusion was discontinued for 1 h and restarted at 50% of the previous setting. If more than two such adjustments were needed, the patient was withdrawn from the study. If analgesia was inadequate, hypotension or orthostasis were treated by discontinuing the study.
Data were collected by a blinded observer before surgery, 4 h after patients arrived in the postanesthesia care unit, and then twice a day between 8:00 and 10:00 AM and between 3:00 and 5:00 PM until the morning of postoperative day 2. Data collection included VAS scores for pain at rest, with cough, and with ambulation (0 = no pain, 100 = worst pain); VAS scores for pruritus (0 = none, 100 = worst pruritus); VAS scores for nausea (0 = none, 100 = worst nausea); sedation scores judged by the observer [9] (1 = wide awake, 2 = drowsy, 3 = dozing intermittently, 4 = mostly sleeping but easily aroused, 5 = awakened only by shaking, 6 = unarousable); supine and upright heart rate and blood pressure; motor strength with surface electromyography; Bromage scale (0 = able to move at hip, knee, and ankle; 1 = able to move at knee and ankle; 2 = able to move ankle; 3 = unable to move either hip, knee, or ankle; and ability to ambulate [yes/no]). Surface electromyography (MyoTrac 2; Thought Technology, Montreal, Canada) was used to assess 5‐s isometric maximal force contraction of the right quadriceps, as previously reported. [10] Electromyography pads (Triode; Thought Technology) were placed on the bilateral quadriceps after the skin was shaved and prepared with an abrasive alcohol pad. The electromyography pads were placed 60% of the distance from the greater trochanter to the knee crease at the lateral joint line. This position was marked and used for all subsequent measurements. Fresh skin preparation and electromyography pads were used for each measurement session. Patients were trained to isometrically contract the quadriceps muscle with the knee fully extended. Measurements were performed in triplicate with a 1‐min rest period between efforts and alternating from side to side. Data were then averaged from each measurement interval. Consumption of PCEA solution was recorded via interrogation of the PCEA device (Pain Management Provider II; Abbott Laboratories, North Chicago, IL).
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Statistical Analysis
Power analysis based on a previous study indicated that 10 participants per group would allow us to detect a 10% difference in lower‐extremity motor block measured by electromyography (P = 0.05, power = 0.8). [1] Repeated‐measures analysis of variance was used to analyze VAS scores for pain, nausea, pruritus, supine and upright heart rates and blood pressures, motor strength measured by electromyography, and PCEA consumption. Fisher's protected least‐significant difference analysis was used for post hoc testing. Nonparametric analysis with the Kruskal‐Wallace test was used to analyze the frequency of nausea, pruritus, sedation, hypotension, orthostasis, and inability to ambulate. Friedman's test was used for post hoc testing. P < 0.05 was considered significant.
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Results

Table 1
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Thirty‐five patients were enrolled, and five patients were excluded because of protocol violations. Patient characteristics were comparable among the groups (Table 1). Visual analog scale pain scores at rest, with cough, or during ambulation were equivalent among the groups (Figure 1). Motor block was significantly more frequent (Table 1) and intense (Figure 2) with the 0.2% ropivacaine‐4 [micro sign]g fentanyl solution. Incidences of pruritus, nausea, and sedation were equivalent among the groups but were mild in severity (Table 1). Episodes and severity of hypotension and orthostatic changes in heart rate or systolic blood pressure were equivalent among the groups (Table 1). The volume of solution used for PCEA differed significantly among the three groups, with the 0.2% ropivacaine‐4 [micro sign]g fentanyl group using the least volume and the 0.05% ropivacaine‐1 [micro sign]g fentanyl group using the most volume (Figure 3). The 0.1% ropivacaine‐2 [micro sign]g fentanyl group used significantly more ropivacaine and fentanyl for PCEA (Figure 4).
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Discussion

Use of a 0.2% solution of ropivacaine increased the frequency and severity of lower‐extremity motor block, including inability to ambulate. Our data suggest that the concentration of ropivacaine solution for PCEA is a primary determinant of motor block. The 0.1% and 0.05% groups used either more or equivalent amounts of ropivacaine, yet these patients had less motor block than those in the 0.2% group. We can provide two potential explanations for increased motor block with increased concentration of ropivacaine solution. First, the 0.1% and 0.05% groups used a greater volume of PCEA solution. Epidural administration of increasing volumes of radiographic contrast results in greater cephaled spread within the epidural space. [11] Greater epidural distribution of the 0.1% and 0.05% solutions may have resulted in less drug mass of ropivacaine at the lumbar spinal segments innervating lower‐extremity motor function.
Another potential explanation for increased efficacy of motor block with the higher concentration of ropivacaine is better penetration of spinal cord motor tracts. A previous animal study observed greater penetration of spinal cord tracts with increasing concentrations of the same dose of epidural bupivacaine. [12] These observations were correlated with an increased efficacy of blocking transmission of somatosensory‐evoked potentials. In a similar manner, the increased concentrations of ropivacaine used in our patients may have produced increased motor block through increased penetration into spinal cord motor areas.
Ours is the first study to evaluate rigorously the effects of concentration of ropivacaine‐fentanyl on motor block with PCEA. Bupivacaine is a local anesthetic that is structurally similar to ropivacaine and is also popular for epidural analgesia. We suspect that decreased concentrations of bupivacaine‐fentanyl would also provide decreased motor block, but few data are available to determine an optimal concentration of bupivacaine or to compare ropivacaine with bupivacaine for epidural analgesia.
We placed our epidural catheters in low thoracic or lumbar vertebral interspaces, which is typical clinical practice for patients undergoing lower abdominal surgery. However, placement of epidural catheters in such proximity to lumbar spinal segments providing motor innervation to the lower extremities appears to increase the risk of motor block when compared with more cephalad placement. [13] We suspect that more cephalad placement of epidural catheters would reduce the incidence and severity of lower‐extremity motor block from all concentrations of ropivacaine‐fentanyl. However, at this time, there are no other clinical studies that have evaluated the use of ropivacaine and fentanyl for PCEA for comparison.
We observed equivalent analgesia at rest, with cough, and during ambulation in all three groups. Previous studies proposed theoretical reasons for improved analgesia with dilution of lipid‐soluble local anesthetic (bupivacaine) [5] and lipid‐soluble opioids (fentanyl and sufentanil). [6‐8] Administration of a high‐volume‐low‐concentration dose of bupivacaine could produce more extensive sensory block as a result of the use of a larger volume of solution. A similar explanation has been proposed for greater analgesic efficacy from dilution of fentanyl or sufentanil for epidural analgesia. Greater anatomic spread of dilute opioid solutions within the epidural space has been proposed to allow interaction with a greater surface area of opioid receptors. However, clinical studies evaluating the use of epidural infusions of bupivacaine‐sufentanil as a high‐volume‐low‐concentration versus low‐volume‐high‐concentration solution have found conflicting results. One study observed no analgesic differences between groups, [7] whereas a different study observed a greater need for epidural supplementation only during the first postoperative day in the low‐volume‐high‐concentration group. [8] Our study differs considerably from previous studies because we used PCEA for postoperative analgesia. Previous experience with PCEA indicates that provision of self‐titrated analgesia allows most patients to achieve similar levels of comfort despite differences in analgesic solution. [14] Although our study lacks sufficient power to assess analgesic differences, we speculate that our use of PCEA rather than continuous epidural infusion may minimize possible analgesic differences between solutions.
Because the use of concentrations less than 0.2% ropivacaine‐4 [micro sign]g fentanyl decreased motor block without affecting analgesic efficacy, a 0.1% ropivacaine‐2 [micro sign]g fentanyl or 0.05% ropivacaine‐1 [micro sign]g fentanyl solution may be preferable for PCEA via a low thoracic or lumbar catheter. Use of the 0.1% ropivacaine‐2 [micro sign]g fentanyl solution resulted in consumption of less PCEA solution than the 0.05% ropivacaine‐1 [micro sign]g fentanyl solution. The lower volume of solution consumed with the 0.1% ropivacaine‐2 [micro sign]g fentanyl solution provides a practical advantage in that fewer containers of PCEA solution are required for each day of PCEA use. This could result in fewer administration errors and decreased pharmacy preparation costs. Conversely, use of the 0.05% ropivacaine‐1 [micro sign]g fentanyl solution resulted in less consumption of ropivacaine and fentanyl. Use of less drug could decrease pharmacy acquisition costs. Although we did not observe differences in side effects in the 0.01% ropivacaine‐2 [micro sign]g fentanyl versus 0.05% ropivacaine‐1 [micro sign]g fentanyl solutions, use of less drug could result in fewer dose‐dependent side effects from ropivacaine‐fentanyl. [15]
In conclusion, concentrations less than 0.2% ropivacaine‐4 [micro sign]g fentanyl decreased motor block without altering analgesia or other side effects. Use of a 0.1% ropivacaine‐2 [micro sign]g fentanyl or 0.05% ropivacaine‐1 [micro sign]g fentanyl solution for PCEA appears preferable for analgesia after lower abdominal surgery.
The authors thank Carol A. Stephenson, R.N., for assistance with this study.
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Appendix 1

Initial Patient‐controlled Epidural Analgesia Device Settings and Adjustments
1. 0.2% ropivacaine‐4 [micro sign]g/ml fentanyl Background infusion rate = 2 ml/h Bolus dose = 1 ml For inadequate analgesia (VAS score at rest > 50 of 100), give 2‐ml loading dose and increase background infusion by 1 ml/h. If more than two adjustments are needed in a 24‐h period, call the Anesthesia Pain Service.
2. 0.1% ropivacaine‐2 [micro sign]g/ml fentanyl Background infusion rate = 4 ml/h Bolus dose = 2 ml For inadequate analgesia (VAS score at rest > 50 of 100), give 4‐ml loading dose and increase background infusion by 2 ml/h. If more than two adjustments are needed in a 24‐h period, call the Anesthesia Pain Service.
3. 0.05% ropivacaine‐1 [micro sign]g/ml fentanyl Background infusion rate = 8 ml/h Bolus dose = 4 ml For inadequate analgesia (VAS score at rest > 50 of 100), give 8‐ml loading dose and increase background infusion by 4 ml/h. If more than two adjustments are needed in a 24‐h period, call the Anesthesia Pain Service.
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Appendix 2

Standardized Monitoring and Treatment of Side Effects
1. No other analgesics or sedative‐hypnotics are to be given without notifying the Pain Service.
2. Treatment of side effects
Respiratory depression: If the respiratory rate is <=or to 8 breaths/min and the patient cannot be aroused, give naloxone.
0.1 mg intravenous STAT (may repeat 3 times). Call the Pain Service.
Respiratory rate <or= to 10, call the Pain Service.
Nausea and vomiting: 0.5 mg droperidol given intravenously every 4 h as needed followed by 4 mg odansetron given intravenously every 4 h as needed.
Itching: 25‐50 mg diphenhydramine given intravenously or orally every 4 h as needed, followed by 2 mg nalbuphine given intravenously every 6 h as needed.
Maintain intravenous access for 2 h after epidural infusion is discontinued.
3. Vital signs Respiratory rate, depth of consciousness, blood pressure, and heart rate should be measured every h for 12 h, every 2 h for 12 h, and every 4 h thereafter. If systolic blood pressure is less than 90 mmHg, call the Pain Service. Check level of sensory block every 8 h, and notify the Pain Service for T‐4 or rising sensory level.
4. Activity: Assisted ambulation only. Call the Pain Service for motor weakness.
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REFERENCES

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2. Etches RC, Writer WD, Ansley D, Nydahl PA, Ong BY, Lui A, Badner N, Kawolski S, Muir H, Shukla R: Continuous epidural ropivacaine 0.2% for analgesia after lower abdominal surgery. Anesth Analg 1997; 84:784-90

3. Turner G, Scott DA: A comparison of epidural ropivacaine infusion alone and with three different concentration of fentanyl for 72 hours of postoperative analgesia following major abdominal surgery (abstract). Reg Anesth 1998; 23:A39

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7. Laveaux MM, Hasenbos MA, Harbers JB, Liem T: Thoracic epidural bupivacaine plus sufentanil: High concentration/low volume versus low concentration/high volume. Reg Anesth 1993; 18:39-43

8. Snijdelaar DG, Hasenbos MA, van Egmond J, Wolff AP, Liem TH: High thoracic epidural sufentanil with bupivacaine: Continuous infusion of high volume versus low volume. Anesth Analg 1994; 78:490-4

9. Liu S, Chiu AA, Neal JM, Carpenter RL, Bainton BG, Gerancher JC: Oral clonidine prolongs lidocaine spinal anesthesia in human volunteers. Anesthesiology 1995; 82:1353-9

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Keywords:
Electromyography; local anesthetics; opioids; postoperative pain.

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