Many different modes of analgesia after thoracic surgery have been used . Epidural fentanyl infusions are used frequently for postoperative analgesia [2-6]. The addition of epinephrine prolongs the duration of bolus epidural injections of fentanyl [7,8]. We hypothesized that adding epinephrine may decrease systemic absorption of fentanyl and decrease infusion requirements . In addition, we theorized that epinephrine has alpha2-agonist properties, which may result in synergistic effects with opioids. The analgesia properties of epinephrine are supported by studies in spinal cord-transected cats, wherein epinephrine suppressed noxiously evoked neuron activity in the dorsal horn . This study was designed to evaluate the use of epinephrine as an adjunct with continuous thoracic epidural infusions of fentanyl. Our hypothesis was that the addition of epinephrine would result in an opioid-sparing effect.
After Institutional Review Board approval and written, informed consent, 38 patients scheduled for elective posterolateral thoracotomy were studied. Exclusion criteria included contraindications to insertion of an epidural catheter, ischemic heart disease, cardiorespiratory disease necessitating postoperative ventilation, inability to communicate in English, and emergency surgery.
Patients were instructed in the use of a visual analog scale (VAS; a vertical line wherein 0 = no pain and 10 = worst pain ever) . Spirometry was measured on three occasions in the sitting position, and the best values of forced expiratory volume in 1 s and forced vital capacity were recorded as baseline values. Vital signs, including mean blood pressure (MBP) and heart rate (HR), were averaged from two separate readings.
All patients received a standardized general anesthetic. premedication consisted of diazepam (0.1 mg/kg) orally. An epidural catheter was inserted at the midthoracic level (T7-9 interspace). A test dose consisting of 3 mL of 2% lidocaine containing micro gram of epinephrine was given. The epidural placement was confirmed by demonstrating a band of analgesia in the thoracic dermatomes. Anesthesia was induced with intravenous sufentanil (0.3 micro gram/kg), d-tubocurare (0.05 mg/kg), thiopental (3-5 mg/kg), and succinylcholine (1.5 mg/kg). The trachea was intubated, and anesthesia was maintained with isoflurane titrated to maintain the MBP within 20% of baseline. An epidural infusion of 2% carbonated lidocaine (5 mL/h) was used for the operative procedure. Vecuronium was used for muscle relaxation, and residual neuromuscular blockade was reversed with glycopyrrolate and neostigmine intravenous (IV). Surgery was completed by one of two surgeons using similar techniques. The thoracotomy incision was made at the T6-7 level. Posterolateral chest tubes were inserted in all patients with the exception of two patients undergoing pneumonectomies (one patient in each group).
Patients were randomized using a Table ofrandom digits to one of two groups. One group received fentanyl 5 micro gram/mL for the bolus and infusion epidural solution. The second group received fentanyl 5 micro gram/mL and epinephrine 3.33 micro gram/mL for all epidural solutions. Randomization and preparation of study drugs were prepared by a research assistant. All solutions were prepared with identical syringes and labels to maintain the blinding of the study.
After arrival in the recovery room (time 0) patients received an epidural bolus of fentanyl 0.5 micro gram/kg with or without epinephrine. An infusion was then initiated at 0.5 micro gram centered dot kg-1 centered dot h-1. VAS scores were assessed at 15-min intervals. If pain control was inadequate (VAS > 4), then a fentanyl bolus of 0.25 micro gram/kg was administered, and infusion was increased by 0.25 micro gram centered dot kg-1 centered dot h-1. The maximum bolus dose was 2 micro gram/kg and 2 micro gram centered dot kg-1 centered dot h-1 for infusion. If patients had no pain with the initial fentanyl bolus and infusion, the infusion rate was decreased to a minimum dose of 0.25 micro gram centered dot kg-1 centered dot h-1. Once comfortable in the recovery room, patients were assessed using VAS scores every 30 min and discharged to the ward after a minimum of 4 h. They required 2 h of effective analgesia (VAS < 4) before being discharged to the postsurgical ward. This protocol allowed for minimum effective fentanyl infusions to be established.
On the hospital ward, patients were reassessed at 24, 48, and 72 h postoperatively. At these assessments, VAS scores were performed at rest and with mobilization or coughing. The infusion rate was decreased by 25% at 24 and 48 h if the VAS score with mobilization or coughing was <4. If breakthrough pain followed a decrease in infusion, the rate was restored to the previous level. If breakthrough pain occurred within the first 24 h, infusion was increased by 0.25 micro gram centered dot kg (-1) centered dot h-1.
Once on the postsurgical ward, monitoring was completed by the surgical nurses. If patients complained of pain, the investigator was notified and a decision was made regarding any adjustments to the infusion rates. Routine postoperative care included respiratory rate monitoring at hourly intervals for the first 24 h and thereafter every 4 h. Patients received acetaminophen for nonsurgical pain (at a site other then along the incision). No other analgesics or sedatives were allowed during the study.
The following data were collected and compared with baseline values: spirometry, MBP, and HR.
Fentanyl plasma concentrations were measured at regular intervals after the initiation of fentanyl infusion in each patient (0.5, 1, 2, 3, 4, 24, 48, and 72 h). Samples were centrifuged immediately and frozen at -30 degrees C for later analysis. Plasma fentanyl concentrations were determined using a commercial radioimmunoassay kit (Janssen Laboratories, Beerse, The Netherlands) . The assay was sensitive to 0.1 ng/mL, with intraassay and interassay coefficients of variation of 6.0% and 6.9%, respectively, at 1.0 ng/mL.
Side effects were assessed by patient interview at 24-h intervals, and severity was graded by assessing need for therapy. Side effects were graded as none = 0, mild requiring no treatment = 1, and severe requiring treatment = 2. Data were collected on the following side effects: nausea, pruritus, dizziness, headache, and backache. Nausea was treated with metoclopramide 10 mg IV every 6 h as required. Severe pruritus was treated with intermittent doses of naloxone 40 micro gram IV. Respiratory depression was defined as a respiratory rate < 10 breaths/min. This was managed by discontinuing the epidural infusion until the respiratory rate was >10 and restarting infusion with a 25% reduction in dose. Urinary retention was graded as follows: 0 = none; 1 = mild hesitancy; 2 = straight catheter required; and 3 = Foley catheter required. Somnolence was graded as follows: 1 = oriented and initiates conversation; 2 = responds to all forms of conversation, is well oriented, but feels sleepy and does not initiate conversation; 3 = responds to verbal command and painful stimulation, but is disoriented and does not initiate conversation; 4 = responds to painful, but not to verbal, communication; and 5 = unresponsive to verbal command or painful stimulation. Satisfaction scores were as follows: 1 = I am completely satisfied with my analgesia and feel no improvements could be made; 2 = I am mostly satisfied with my analgesia, but feel that some improvements could make it better; 3 = I am mostly dissatisfied with my analgesia and feel that many improvements are required; and 4 = I am completely dissatisfied with my analgesia postoperatively. Somnolence scores of 3 were managed by a 25% reduction in the epidural infusion rate. Patients with somnolence scores of >3 had the epidural infusion discontinued, and the patient was immediately assessed.
All data are presented as the mean +/- SEM, with the exception of the frequency distribution of patient demographics and side effects. A two-tailed t-test was used to compare demographic data, except for shoulder pain, acetaminophen usage, and gender where chi squared analysis was used . Fentanyl plasma levels, fentanyl requirements, spirometry, and vital signs were compared by multivariate repeated-measured analysis of variance (ANOVA) . In addition, univariate ANOVA was used at specific times to differentiate differences in fentanyl requirements and plasma levels. Side effects and pain scores were analyzed using Wilcoxon ranked sum scores. A P value < 0.05 was considered significant in all cases.
Of the 38 patients enrolled, four patients were excluded from the study (two patients because of extensive chest wall resections, one patient because of underlying sleep apnea, and the randomization code was lost on one patient). Data for 34 patients were analyzed: 18 in the group were given fentanyl and epinephrine, and 16 in the group were given fentanyl alone.
There was no significant differences in demographics between the two groups except for patient weight Table 1. The difference in patient weight was not related to obesity, because body mass index was similar in the two groups. The effect of patient weight was removed by normalizing fentanyl requirements for weight. The two groups were similar with respect to type and duration of surgery, incidence of shoulder pain, and requirement for acetaminophen.
There was good pain control in both groups, with no difference in VAS pain scores at rest or with mobilization at any time Figure 1.
The mean hourly fentanyl requirements were significantly lower in the epinephrine group (repeated-measures ANOVA, P = 0.005). This difference was significant from 1 to 48 h postoperatively (univariate ANOVA, P < 0.05; Figure 2). In addition, epinephrine resulted in a reduction in the number of fentanyl boluses required for equivalent analgesia (mean number of boluses in epinephrine group = 2.7 vs 4.4 in group without epinephrine, P = 0.004 Wilcoxon two-sample test).
A total of 239 blood samples were collected and analyzed for plasma fentanyl concentrations (87.8% data recovery). Plasma fentanyl concentrations were significantly lower in the epinephrine group (repeated-measures ANOVA, P = 0.007). This difference was significant at all times measured, except at 72 h (univariate ANOVA, P < 0.05; Figure 2).
Patients had severely impaired pulmonary function after thoracotomy [2,14,15]. We found similar reductions of forced expiratory volume in 1 s and forced vital capacity Figure 3, with no difference between the two groups.
There was no difference in hemodynamics, with MBP and HR within 20% of baseline at 24, 48, and 72 h Figure 4.
The incidence of adverse effects was similar in the two groups Table 2. Most adverse effects were mild, requiring no treatment. Urinary retention occurred frequently (62%). A high incidence of urinary retention was observed early in the study, and, thereafter, Foley catheters were inserted during the operative procedure. Respiratory depression occurred in one 59-yr-old male patient in the no epinephrine group at 11 h postoperatively, necessitating stopping the epidural infusion for 5 h. The epidural infusion was at 135 micro gram/h when a respiratory rate of 10 with a somnolence score of 2 was noted. The infusion was reinstituted when the respiratory rate was >10, and the patient suffered no further adverse effects. Severe nausea and emesis unresponsive to treatment occurred in one patient in the epinephrine group. This required withdrawal of this patient from the study. Pruritus was a common side effect and occurred in the thoracic dermatomal distribution. Most episodes of pruritus were mild, with two patients in the epinephrine group requiring treatment (one patient requiring one dose of naloxone and the other patient requiring two doses of naloxone).
There were few problems encountered during epidural placement. An inadvertent dural puncture occurred in one patient whose epidural was successfully placed with a second attempt at a interspace lower. With the initial placement of the epidural catheter, two patients had bleeding that was successfully treated by withdrawing the catheters 1 cm. There were no other problems in threading the catheters that were placed on average 3 cm into the epidural space.
The most frequent complication was epidural catheters dislodging prematurely, which occurred in seven patients (21%, two in the epinephrine group and five in the no epinephrine group). As a result, not all patients completed the study. At 48 h, there were 17 patients in the epinephrine group and 13 in the no epinephrine group. At 72 h, there were 16 and 11 patients, respectively. The loss of data was taken into consideration in statistical analysis. Fentanyl requirements and plasma concentrations were analyzed by both multivariate repeated-measures ANOVA and univariate ANOVA used at specific times. This maximizes the data acquired, because multivariate repeated-measures ANOVA is restricted to patients without missing data points.
There was no significant somnolence in either group. Satisfaction scores were similar in both groups, with all patients completely or mostly satisfied with their analgesia (scores = 1-2).
This prospective study evaluated the addition of epinephrine as an adjunct to continuous thoracic epidural fentanyl infusions after thoracotomy. Previous studies have shown that epinephrine prolongs analgesia when added to epidural fentanyl given by bolus injection [7,8]. In these studies, concentrations of epinephrine varied from 2.5 to 5 mu/mL [7,8]. We chose an epinephrine concentration of 3.33 micro gram/mL based on these studies to minimize any side effects related to a continuous epinephrine infusion. The use of epinephrine as an adjunct to continuous epinephrine fentanyl infusions has not been reported previously. Our study shows that epinephrine reduces dose requirements for epidural fentanyl infusions and that this is associated with decreased plasma fentanyl concentrations.
We chose to administer fentanyl with and without epinephrine via a thoracic epidural catheter. Previous studies comparing intravenous versus epidural fentanyl after thoracotomy have shown conflicting results, suggesting that the position of the epidural catheter may be important [3,15,16]. Studies comparing lumbar epidural versus intravenous fentanyl infusions have found no difference in opioid requirements  and similar opioid blood concentrations [16,17]. In contrast, studies comparing thoracic epidural fentanyl with intravenous infusions have found a reduction in fentanyl requirements [3,15] and opioid blood concentrations in the epidural group . Maximum efficacy of epidural fentanyl is achieved by infusions at, or very near, the dermatomal level of the surgical incision.
In our study, epinephrine significantly reduced fentanyl dose requirements (1.19 +/- 0.11 group without epinephrine vs 0.82 +/- 0.07 micro gram centered dot kg-1 centered dot h-1 epinephrine group). Epinephrine also reduced the number of fentanyl boluses required for equivalent and adequate analgesia. The reduced dose requirements significantly decreased plasma fentanyl concentrations. The plasma fentanyl concentrations reached relatively stable levels by 24 h postoperatively Figure 2. Mean plasma concentrations at steady-state (24-72 h) were 0.91 +/- 0.13 ng/mL in the epinephrine group and 1.65 +/- 0.23 ng/mL in the no epinephrine group. The systemic plasma fentanyl concentration required for analgesia after intravenous injection is 1.6-1.8 ng/mL [16,18,19]. Therefore, the plasma fentanyl concentrations in the epinephrine group were too small to provide effective analgesia. This suggests that, when epinephrine is added to epidural fentanyl, the reduced dose requirements are caused by the effects of fentanyl, epinephrine, or both on the spinal cord. This may be caused by epinephrine-reducing vascular uptake, resulting in higher and prolonged cerebral spinal fluid fentanyl concentrations. This has been suggested when epinephrine is used as an adjunct to sufentanil  or morphine . Another potential mechanism is inhibition of pain transmission  and a synergistic interaction with opioids because of epinephrine binding to alpha2-receptors in the dorsal horn. The design of this study does not allow us to determine whether the fentanyl sparing of epinephrine occurs because of decreased vascular uptake of fentanyl or from alpha2-agonist activity.
Epidural opioids have been reported to improve pulmonary function after thoracotomy when compared with intramuscular or intravenous administration of opioids [6,14,15]. We found no difference in postoperative pulmonary function in the two groups.
In this study, there was no difference in side effects. The incidence of nausea was similar in both groups; however, severe nausea unresponsive to metoclopramide occurred in one patient receiving epidural fentanyl and epinephrine. It is speculation as to whether this is a result of epinephrine; however, this is not supported by other studies [7,8]. Pruritus became more severe with the addition of epinephrine, but did not reach statistical significance. Previous studies have shown an increased incidence of pruritus when epinephrine is added to epidural fentanyl; the etiology of this is unclear [7,8]. There was one episode of respiratory depression in the group without epinephrine. Respiratory depression with epidural fentanyl is considered rare, but it certainly does occur. It has been a traditional belief that respiratory depression from epidural fentanyl occurs because of cephalad migration of fentanyl via the cerebrospinal fluid to the brainstem . However, since there is substantial vascular up-take of fentanyl from the epidural space, it is possible that systemic levels are important in determining respiratory depression. In an animal model, Bernards and Sorkin  have demonstrated that there is minimal rostral spread of epidural fentanyl by measuring concentrations in spinal cord dialysate. This suggests that systemic concentrations may be an important determinant of supraspinal effects, such as respiratory depression. If this hypothesis is correct, then reduced plasma fentanyl concentrations would be inherently safer. A larger study is necessary to demonstrate any difference in rare events, such as respiratory depression.
In summary, we found that epinephrine decreased fentanyl requirements for continuous thoracic epidural infusions after thoracotomy. This reduction in fentanyl requirements was associated with reduced fentanyl plasma concentrations. The addition of epinephrine was not associated with any difference in hemodynamics, spirometry, side effects, or patient satisfaction.
We thank Douglas Craig, FRCPC, and Robert Hudson, FRCPC, for reviewing this manuscript; Alan Sandler, FRCPC, for his assistance in obtaining a laboratory for plasma fentanyl analysis; and Barb Filuk and Maureen Cumming for preparation of study drugs.
1. Kavanagh BP, Katz J, Sandler AN. Pain control after thoracic surgery. Anesthesiology 1994;81:737-59.
2. Benzon HT, Wong HY, Belavic AM, et al. A randomized doubleblind comparison of epidural fentanyl infusion versus patient controlled analgesia with morphine for postthoracotomy pain. Anesth Analg 1993;76:316-22.
3. Salomaki TE, Laitinen JO, Nuutinen LS. A randomized doubleblind comparison of epidural versus intravenous fentanyl infusion for analgesia after thoracotomy. Anesthesiology 1991;75:790-5.
4. Badner NH, Sandler AN, Koren G, et al. Lumbar fentanyl infusions for post-thoracotomy patient: analgesic, respiratory, and pharmacokinetic effects. J Cardiothorac Anesth 1990;4:543-51.
5. Welchew EA, Thornton JA. Continuous thoracic epidural fentanyl: a comparison of epidural fentanyl with intramuscular papaveretum for postoperative pain. Anaesthesia 1982;37:309-16.
6. Lomessy AL, Magnin C, Viale J, et al. Clinical advantages of fentanyl given epidurally for postoperative analgesia. Anesthesiology 1984;61:466-9.
7. Robertson K, Douglas JM, McMorland GH. Epidural fentanyl, with and without epinephrine for post-Cesarian section analgesia. Can Anaesth Soc J 1985;32:502-5.
8. Welchew EA. The optimum concentration for epidural fentanyl (a randomized, double-blind comparison with and without 1:200,000 adrenalin). Anaesthesia 1983;38:1037-41.
9. Collins JG, Matsumoto M, Kitahata LM. Suppression by spinally administered epinephrine of noxiously evoked dorsal horn neuron activity in cats. Evidence for spinal epinephrine analgesia. Anesth Analg 1983;62:253-4.
10. Revill SI, Robinson JO, Rosen M, Hogg MIJ. The reliability of a linear analogue for evaluating pain. Anaesthesia 1976;31:1191-8.
11. Michiels M, Hendricks R, Heykants J. A sensitive radioimmunoassay for fentanyl. Eur J Cin Pharmacol 1977;12:153-8.
12. Johnson R, Bhattacharyya G. Statistics principles and methods. New York: John Wiley and Sons, 1985.
13. Freund RJ, Littell RC, Spector PC. SAS system for linear model. Cary, NC: SAS Institute, Inc., 1986.
14. Shulman M, Sandler AN, Bradley JW, et al. Postthoracotomy pain and pulmonary function following epidural and systemic morphine. Anesthesiology 1984;61:569-75.
15. Guinard JP, Mavrocordatos P, Chiolero R, Carpenter RL. A randomized comparison of intravenous versus lumbar and thoracic epidural fentanyl for analgesia after thoracotomy. Anesthesiology 1992;77:1108-15.
16. Sandler AN, Stringer D, Panos L, et al. A randomized, doubleblind comparison for lumbar epidural and intravenous fentanyl infusions for postthoracotomy pain relief. Anesthesiology 1992;77:626-34.
17. Baxter AD, Laganiere S, Samson B, et al. A comparison of lumbar epidural and intravenous fentanyl infusions for post-thoracotomy analgesia. Can J Anaesth 1994;41:184-91.
18. Nimmo WS, Todd JG. Fentanyl by constant infusion for postoperative analgesia. Br J Anaesth 1985;57:250-4.
19. Loper KA, Ready LB, Downey M, et al. Epidural and intravenous fentanyl infusions are clinically equivalent after knee surgery. Anesth Analg 1990;70:72-5.
20. Klepper ID, Sherrill DL, Boetger CL, Bromage PR. Analgesic and respiratory effects of extradural sufentanil in volunteers and the influence of adrenalin as an adjuvant. Br J Anaesth 1987;59:1147-56.
21. Bromage PR, Camporesi EM, Durant PA, Neilsen CH. Influence of epinephrine as an adjuvant to epidural morphine. Anesthesiology 1982;58:257-62.
22. Etches RC, Sandler AN, Daley MD. Respiratory depression and spinal opioids. Can J Anaesth 1989;36:165-85.
23. Bernards CM, Sorkin LS. Radicular artery blood flow does not redistribute fentanyl from the epidural space to the spinal cord. Anesthesiology 1994;80:872-8.