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ANALGESIA

Epinephrine 4 µg/mL Added to a Low-Dose Mixture of Ropivacaine and Fentanyl for Lumbar Epidural Analgesia After Total Knee Arthroplasty

Johannes G. Förster, MD^*, Hilkka M. Lumme, MD, Vilja J. Palkama, MD, PhD, Per H. Rosenberg, MD, PhD^*, and Mikko T. Pitkänen, MD, PhD

From the *Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Hospital, Finland; and Department of Anesthesia, Orton Orthopedic Hospital, Invalid Foundation, Helsinki, Finland.

Address correspondence to Johannes G. Förster, MD, Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Hospital, Haartmaninkatu 4, PO Box 340, 00029 Helsinki, Finland. Address e-mail to johannes.forster{at}hus.fi.

Abstract

BACKGROUND: Epinephrine 2 µg/mL added to a local anesthetic-opioid mixture has been found to improve postoperative continuous epidural analgesia at the thoracic (TEA) but not at lumbar (LEA) level. Therefore, we studied whether a higher dose of epinephrine could improve LEA.

METHODS: Patients received LEA comprising of ropivacaine 1.8 mg/mL and fentanyl 3 µg/mL either without (group RF, n = 32) or with epinephrine 4 µg/mL (group RFE, n = 31) for 2 days after total knee arthroplasty. Rescue pain medication consisted of epidural top-ups (study mixture) and parenteral oxycodone.

RESULTS: Total amounts of epidurally administered drugs were significantly higher in group RFE. Otherwise, the groups did not differ significantly regarding pain relief and side effects.

CONCLUSIONS: As part of the multimodal pain treatment used, the epidural adjuvant epinephrine 4 µg/mL (12–32 µg/h) did not improve LEA after total knee arthroplasty.

Epinephrine 2 µg/mL has improved thoracic continuous epidural analgesia (TEA) when administered together with mixtures of bupivacaine-fentanyl1 or ropivacaine-fentanyl.2 However, this epinephrine concentration was found to be ineffective as an adjuvant in lumbar continuous epidural analgesia (LEA) comprising ropivacaine and fentanyl.3 We hypothesized that administering a higher epinephrine dose may increase the availability of epinephrine at the spinal cord ₂-receptor sites resulting in enhanced epidural analgesia.4–6 Therefore, we studied whether epinephrine 4 µg/mL improves the efficacy (reduced rescue pain medication requirement as a primary outcome end point) of ropivacaine-fentanyl LEA after total knee arthroplasty (TKA).

METHODS

After receiving Institutional Ethics Committee and National Agency for Medicines approval and patients’ written consent, 70 patients (85 yr, ASA class I–III) undergoing primary, unilateral TKA were enrolled to this randomized and double-blind investigation. Exclusion criteria were contraindications to neuraxial anesthesia, allergy to nonsteroidal antiinflammatory drugs, history of heart (New York Heart Association class III–IV), renal or hepatic insufficiency, psychiatric condition, and body mass index > 36 kg/m². The timing of thromboprophylaxis in relation to placement and removal of the epidural catheter followed published guidelines.7 Patients were premedicated with oral diazepam depending on age and weight.

At the L2-3 or L3-4 interspace, an epidural catheter (18-gauge epidural minipack® Portex Ltd., Hythe, Kent, UK) was advanced 3–5 cm into the epidural space. After that, spinal anesthesia was provided one interspace below using 3 mL ropivacaine (Naropin®, AstraZeneca, Espoo, Finland) 7.5 mg/mL. During surgery, anesthesia was supplemented with epidural bolus injections of ropivacaine 7.5 mg/mL, if necessary.

In the epinephrine group (RFE, n = 35), the epidural mixture consisted of ropivacaine 1.8 mg/mL, fentanyl 3 µg/mL (Fentanyl®, B. Braun, Helsinki, Finland), and epinephrine 4 µg/mL (Adrenalin®, Leiras, Helsinki, Finland; formula containing sodium edetate and sodium metabisulfite). In the control group (RF, n = 35), an identical mixture, but without epinephrine, was used. In the postanesthesia care unit, LEA was started when the sensory blockade had descended to Th10-L1 and motor function of the lower extremities started to recover. After a 5-mL bolus of the study solution, the infusion was started (5 mL/h); the rate was adjusted within the range 3–8 mL/h. The infusion rate was increased 1–2 mL/h if the pain score was >3 evaluated on a 10 cm long visual analog scale (VAS) score from 0 to 10. Infusion rate was decreased in the event of pronounced motor blockade, hypotension, or bradycardia. The infusion was scheduled to continue until 12:00 on the second postoperative day. Amounts for epidurally administered drugs were calculated retrospectively based on the infusion rates marked in the epidural forms (forms were kept bedside at all the times and nurses were instructed to meticulously note in the form whenever the infusion rate was changed).

Study variables were recorded every hour for the first 3 h of the epidural infusion, and thereafter at 06:00, 12:00, 18:00, and 24:00 (±30 min). Respiratory rate, arterial blood pressure, and heart rate were recorded just as measured at these predetermined times. However, for pain intensity at rest and during motion, satisfaction with pain treatment regimen, motor blockade, sedation, pruritus, and nausea and vomiting, the highest or "worst" values observed and recorded between the past and the current interview were forwarded to statistical analysis. Finally, the overall satisfaction concerning the pain management regimen was assessed on a numerical scale from 0 (worst) to 10 (best).

Patients received acetaminophen 1 g IV when LEA was started and, thereafter, acetaminophen 1 g orally every 8 h. Additionally, a nonsteroidal antiinflammatory drug was started in the evening after the operation. First-line rescue pain medication was a 5-mL bolus of the epidural mixture. Two boluses within 1 h were allowed. Concomitantly, the epidural infusion rate was increased by 1–2 mL/h. If epidural boluses did not provide sufficient pain relief (VAS 3), oxycodone 0.03 mg/kg IV or 0.05–0.07 mg/kg IM was given.

Groups were compared with contingency table analyses, with parametric or nonparametric tests, and with two-way repeated-measures analysis of variance, as appropriate. P < 0.05 was considered statistically significant. As no epidural analgesia studies with similar drug mixture and doses in patients after TKA were available, we based the sample size calculation on experience gained during recent clinical practice and two previous studies performed by our group.8,9 With an average rescue oxycodone requirement of 16 mg IM (sd 11 mg) and assuming a mean reduction of 50% as clinically significant, 31 patients per group were found necessary to detect statistical significance ( = 0.05, two sided, power = 80%); we allocated 35 patients to each group to allow for possible drop-outs.

RESULTS

Seven enrolled patients had to be excluded completely from the statistical analysis for failure of LEA (2 in group RF, 2 in group RFE), insufficient LEA (2 in group RFE), and wrong epidural drug mixture because of human error (1 in group RF). The data of another 10 patients (4 in group RF, 6 in group RFE) were included in the statistical analysis until the time of their premature withdrawal (Table 1). Reasons for premature withdrawals were technical problems, postoperative confusion, and protocol violations (premature discontinuation of the epidural infusion, last interview remained undone). Both groups were comparable for patient characteristics and intraoperative data (Table 1, partial data shown). In all patients, surgery could be performed under regional anesthesia as planned; epidural top-ups were needed in a few patients intraoperatively (Table 1).

Table 1 shows the most important details concerning the multimodal pain management regimen including LEA. Significantly larger amounts of drugs were given epidurally in group RFE compared with group RF (Fig. 1); mean (sd) cumulative totals were 283 (68) mL in group RFE versus 243 (70) mL in group RF (difference between means 40 mL [95% CI: 5–75 mL]) at the end of the study infusion (P = 0.025, t-test). The total amounts or number of doses of oxycodone IV and IM were similar in both groups, as were the combined number of oxycodone IV, IM doses, and epidural boluses (Table 1). Median VAS pain scores at rest were 3 at all time points except in group RFE at 24:00 on the day of surgery. Pain scores during motion did not differ significantly between groups apart from at 24:00 on the day of surgery and at 06:00 on the second postoperative day when higher values were seen in group RFE (Fig. 1).

View larger version (21K): [in this window] [in a new window]   Figure 1. Pain scores measured on a visual analog scale (VAS) from 0 (no pain) to 10 (worst pain imaginable) during motion; and amounts of epidurally administered drugs (infused plus boluses) (mL). Group RF without, group RFE with epidural epinephrine. Day 0, 1, and 2 = day of surgery, and first and second postoperative day, respectively. The number of patients decreases over time in accordance to premature drop-outs. In addition, n-numbers vary concerning VAS because pain score during motion was not always assessed at night or when pain was already strong at rest. For VAS pain scores: box plots with median and 25th/75th percentiles, whiskers are 10th/90th percentiles. *Statistically significant differences (P = 0.02 and 0.003, MW-U test). For epidurally administered drugs: symbols are mean with sd. There was a statistically significant interaction between the two factors group and time (P = 0.02, F = 2.4, two-way repeated-measures analysis of variance, premature and total drop-outs excluded, i.e., n = 53). The difference between RF and RFE was statistically significant at all interviews (P = 0.03–0.002, t-test).

No statistically or clinically significant difference in vital variables and side effects was observed between groups (data not shown). No serious side effects were observed. During the study infusion, patients were comparably satisfied with pain treatment except for at 18:00 and 24:00 on the day of surgery when the difference reached statistical significance in favor of group RF (P = 0.02 and 0.048, respectively, ² test). However, at the end of the study, the patients’ overall satisfaction with the pain management regimen was similar in both groups (Table 1).

DISCUSSION

Epinephrine 4 µg/mL (12–32 µg/h) did not reduce the need for epidurally administered drugs and rescue pain medication, nor did it affect side effects, when given as an adjuvant to LEA comprising ropivacaine (1.8 mg/mL) and fentanyl (3 µg/mL) after TKA. RFE patients received significantly more epidurally administered drugs, a difference that continued to increase over the two study days. Two factors might have contributed to this finding. First, the RFE patients received intraoperative epidural top-ups less frequently than the RF patients (Table 1). Second, the epidural infusion was started somewhat earlier during the day in group RFE compared with group RF (Table 1). Both these differences likely occurred by chance. However, chance does not explain why the difference in epidural consumption continued to become more pronounced over the two study days. Nevertheless, from a clinical point of view, the difference between means was small (40 mL [95% CI: 5–75 mL] after 2 days). Although pain scores were higher and patients’ satisfaction lower in group RFE at two predetermined interview points, there were no significant differences in total oxycodone amounts and number of rescue pain medication doses, breakthrough pain episodes, and patients’ overall satisfaction at the end of the study.

The present findings contrast studies in which epinephrine as an adjuvant to TEA has proved beneficial.1,2,10,11 Possible reasons for this discrepancy between TEA and LEA have been discussed earlier,3,12 e.g., the dissimilar distances between the site of epidural drug administration and the spinal cord ₂-receptor site. Furthermore, epinephrine seems to have varying effects on blood flow in different tissues found in the spinal canal.13,14 It may not attain high enough concentrations in epidural fat to produce vasoconstriction, which is one of the assumed mechanisms by which epinephrine may enhance the effect of coadministered local anesthetics and opioids.15 Instead, because of its hydrophilicity, epinephrine might be present in such relatively low concentrations in the epidural fat that it causes vasodilation through β₂-adrenergic receptors.13,16 The net effect of epinephrine added to other drug mixtures used in continuous epidural analgesia may be difficult to generalize when considering the characteristics of the opioids (e.g., lipophilicity) and the local anesthetics (e.g., vasoconstrictive properties)17,18 used in the epidural mixtures. The lack of effect of epinephrine in this study was found under specific conditions and the generalizability of the data is limited.

In conclusion, as an adjuvant component of our multimodal analgesia regimen, epinephrine 4 µg/mL (12–32 µg/h) did not improve lumbar epidural analgesia using ropivacaine and fentanyl after TKA.

ACKNOWLEDGMENTS

We are grateful to the colleagues and nursing staff of the Orton Orthopedic Hospital, Helsinki, Finland, for valuable assistance throughout the study.

Footnotes

Accepted for publication August 23, 2007.

Supported by a grant from the ORTON Research Institute, Invalid Foundation, Helsinki, Finland.

There is no conflict of interest to be disclosed.

Presented in part at the 26th Annual Congress of the European Society of Regional Anaesthesia and Pain Therapy (ESRA), Valencia, Spain, September 12–15, 2007.

Reprints will not be available from the author.

REFERENCES

1. Niemi G, Breivik H. Adrenaline markedly improves thoracic epidural analgesia produced by a low-dose infusion of bupivacaine, fentanyl and adrenaline after major surgery. A randomised, double-blind, cross-over study with and without adrenaline. Acta Anaesthesiol Scand 1998;42:897–909[Web of Science][Medline]
2. Niemi G, Breivik H. Epinephrine markedly improves thoracic epidural analgesia produced by a small-dose infusion of ropivacaine, fentanyl, and epinephrine after major thoracic or abdominal surgery: a randomized, double-blinded crossover study with and without epinephrine. Anesth Analg 2002;94:1598–605[Abstract/Free Full Text]
3. Förster JG, Niemi TT, Aromaa U, Neuvonen PJ, Seppälä TA, Rosenberg PH. Epinephrine added to a lumbar epidural infusion of a small-dose ropivacaine-fentanyl mixture after arterial bypass surgery of the lower extremities. Acta Anaesthesiol Scand 2003;47:1106–13[Web of Science][Medline]
4. Reddy SV, Maderdrut JL, Yaksh TL. Spinal cord pharmacology of adrenergic agonist-mediated antinociception. J Pharmacol Exp Ther 1980;213:525–33[Abstract/Free Full Text]
5. Collins JG, Kitahata LM, Matsumoto M, Homma E, Suzukawa M. Spinally administered epinephrine suppresses noxiously evoked activity of WDR neurons in the dorsal horn of the spinal cord. Anesthesiology 1984;60:269–75[Web of Science][Medline]
6. Curatolo M, Petersen-Felix S, Arendt-Nielsen L, Zbinden AM. Epidural epinephrine and clonidine: segmental analgesia and effects on different pain modalities. Anesthesiology 1997;87:785–94[Web of Science][Medline]
7. Gogarten W, Van Aken H, Büttner J, Riess H, Wulf H, Bürkle H. Neuraxial blockade and thromboembolism prophylaxis/ antithrombotic therapy: revised recommendations of the German Society of Anaesthesiology and Intensive Care. Anaesth Intensivmed 2003;44:218–30
8. Silvasti M, Pitkänen M. Patient-controlled epidural analgesia versus continuous epidural analgesia after total knee arthroplasty. Acta Anaesthesiol Scand 2001;45:471–6[Web of Science][Medline]
9. Förster JG, Rosenberg PH. Small dose of clonidine mixed with low-dose ropivacaine and fentanyl for epidural analgesia after total knee arthroplasty. Br J Anaesth 2004;93:670–7[Abstract/Free Full Text]
10. Baron CM, Kowalski SE, Greengrass R, Horan TA, Unruh HW, Baron CL. Epinephrine decreases postoperative requirements for continuous thoracic epidural fentanyl infusions. Anesth Analg 1996;82:760–5[Abstract]
11. Sakaguchi Y, Sakura S, Shinzawa M, Saito Y. Does adrenaline improve epidural bupivacaine and fentanyl analgesia after abdominal surgery? Anaesth Intensive Care 2000;28:522–6[Web of Science][Medline]
12. Curatolo M. Is epinephrine unfairly neglected for postoperative epidural mixtures? Anesth Analg 2002;94:1381–3[Free Full Text]
13. Bernards CM, Shen DD, Sterling ES, Adkins JE, Risler L, Phillips B, Ummenhofer W. Epidural, cerebrospinal fluid, and plasma pharmacokinetics of epidural opioids (part 2): effect of epinephrine. Anesthesiology 2003;99:466–75[Web of Science][Medline]
14. Kozody R, Palahniuk RJ, Wade JG, Cumming MO, Pucci WR. The effect of subarachnoid epinephrine and phenylephrine on spinal cord blood flow. Can Anaesth Soc J 1984;31:503–8[Web of Science][Medline]
15. Covino BG, Wildsmith JAW. Clinical Pharmacology of Local Anesthetic Agents. In: Cousins MJ, Bridenbaugh PO, eds. Neural Blockade in Clinical Anesthesia and Management of Pain. 3rd ed. Philadelphia: Lippincott-Raven Publishers, 1998:97–128
16. Millet L, Barbe P, Lafontan M, Berlan M, Galitzky J. Catecholamine effects on lipolysis and blood flow in human abdominal and femoral adipose tissue. J Appl Physiol 1998;85:181–8[Abstract/Free Full Text]
17. Cederholm I, Åkerman B, Evers H. Local analgesic and vascular effects of intradermal ropivacaine and bupivacaine in various concentrations with and without addition of adrenaline in man. Acta Anaesthesiol Scand 1994;38:322–7[Web of Science][Medline]
18. Kristensen JD, Karlsten R, Gordh T. Spinal cord blood flow after intrathecal injection of ropivacaine and bupivacaine with or without epinephrine in rats. Acta Anaesthesiol Scand 1998;42:685–90[Web of Science][Medline]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Förster, J. G. Articles by Pitkänen, M. T. Search for Related Content PubMed PubMed Citation Articles by Förster, J. G. Articles by Pitkänen, M. T. Related Collections Pain Mechanisms Clinical Pharmacology Regional Anesthesia Pharmacology