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Department of Anesthesiology, Rikshospitalet University Hospital, Oslo, Norway
Address correspondence and reprint requests to Geir Niemi, Department of Anesthesiology, Rikshospitalet University Hospital, University of Oslo, N-0027 Oslo, Norway. Address e-mail to geir.niemi{at}klinmed.uio.no
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Abstract |
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2-agonist effect of epinephrine would give the same positive pharmacodynamic interaction with ropivacaine and fentanyl during epidural analgesia. In a prospective, randomized, crossover study, a thoracic epidural infusion of ropivacaine 1 mg/mL and fentanyl 2 µg/mL with or without epinephrine 2 µg/mL was given to 12 patients in a double-blinded manner after major thoracic or upper abdominal surgery. Main outcome measures were pain intensity at rest and when coughing, evaluated on a visual analog scale. Extent of sensory blockade was evaluated by determining dermatomal hypoesthesia to cold. Pain increased (P < 0.001) and hypoesthetic dermatomal segments decreased (P < 0.001) when epinephrine was omitted from the triple epidural infusion. After 3 h without epinephrine, pain intensity when coughing was unacceptable despite rescue analgesia. After restarting the triple epidural mixture with epinephrine, pain was again reduced to mild pain when coughing, and the sensory blockade was restored. The mixture with epinephrine caused less nausea and facilitated mobilization. We conclude that epinephrine improves the pain relief and reduces the side effects of a thoracic epidural infusion of ropivacaine and fentanyl after major thoracic or upper abdominal surgery. IMPLICATIONS: Epidural epinephrine markedly improves the pain relief and sensory blockade of a small-dose thoracic epidural infusion of ropivacaine and fentanyl. Nausea was reduced, and mobilization of the patients was facilitated.
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Introduction |
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2-agonists, opioids, and local anesthetics in the substantia gelatinosa of the spinal cord dorsal horn (3). Ropivacaine has an intrinsic vasoconstrictive effect (4), and epinephrine may therefore not have the same pharmacokinetic interaction in a ropivacaine-fentanyl infusion; but a possible spinal cord 2-agonist effect of epinephrine would give the same positive pharmacodynamic interaction with ropivacaine and fentanyl during epidural analgesia. The objective of this study was to evaluate the contribution of epinephrine to the analgesic efficacy and safety of a small-dose epidural mixture with ropivacaine and fentanyl. By removing epinephrine from an optimally titrated epidural infusion of this mixture, we could evaluate its effect on postoperative pain and side effects. |
Methods |
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The study was designed as a prospective, randomized, double-blinded crossover study to evaluate the effects of a thoracic epidural infusion of ropivacaine plus fentanyl with or without epinephrine on pain intensity after major surgery (Fig. 1). Patients scheduled for major thoracic or upper abdominal surgery were selected for the study because these operations cause quite severe pain when the patient coughs (Table 1). In our clinical practice, we titrate the thoracic epidural infusion to optimal analgesia, i.e., minimal pain at rest, only mild pain when coughing (visual analog pain intensity score [VAS] <30 mm on a 100-mm scale), and no leg weakness. After titration to optimal epidural analgesia with the triple component mixture on the day of surgery, patients were randomly allocated to receive one of the two trial epidural analgesic mixtures on the first postoperative day and the alternative epidural mixture on the second postoperative day. Block randomization was performed with a block size of six, by use of random numbers (5). Block size was unknown to the investigators.
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All the patients included were mentally alert, able to understand the instructions, and considered physically able to participate after surgery. They had only mild pain (VAS <30) when coughing, with distinct and stable bilateral upper and lower sensory block levels of dermatomal hypoesthesia to cold (ice cube) covering the surgical wound completely. The epidural infusion rate had been stable for the last 10 h, including occasional PCA bolus doses of 4 mL, and there was no leg weakness or any other side effects of the triple epidural infusion.
Patients were excluded if they had any contraindications to insertion of an epidural catheter, such as infection, anatomical abnormalities of the spine, or full anticoagulation. Also excluded were patients with incomplete or unstable analgesia caused by technical epidural catheter problems, including epidural catheter insertions that were too high or too low.
Before the induction of general anesthesia, an epidural catheter was inserted at an appropriate level between the 6th and 12th thoracic interspace, depending on the site of surgery. A paramedian approach with loss-of-resistance technique was used. The epidural catheter was inserted approximately 5 cm into the epidural space. A test dose of 3 mL of bupivacaine 5 mg/mL (Marcain®; AstraZeneca, Södertälje, Sweden) was injected into the catheter to exclude subarachnoid placement. Light general anesthesia was induced with thiopentone, fentanyl, and cisatracurium and maintained with nitrous oxide in oxygen with a small concentration (0.5–1.0 minimum alveolar anesthetic concentration) of isoflurane plus IV fentanyl as needed.
The epidural catheter was connected to a PCA pump, and our standard epidural mixture containing bupivacaine 1 mg/mL, fentanyl 2 µg/mL, and epinephrine 2 µg/mL was started as a continuous infusion at a rate of 4–8 mL/h. The patients received intermittent epidural bolus injections of 5 mL of bupivacaine 5 mg/mL when blood pressure increased.
After surgery, our standard epidural mixture containing bupivacaine (6) was replaced with a mixture consisting of ropivacaine 1 mg/mL, fentanyl 2 µg/mL, and epinephrine 2 µg/mL. This thoracic epidural infusion was continued with infusion rates of 5–13 mL/h, titrated to obtain satisfactory pain relief. The patients were allowed to self-administer one 4-mL bolus of the epidural analgesic mixture, up to twice per hour. All patients received rectal acetaminophen 1 g, every sixth hour. In the morning of the first and second postoperative days, the acetaminophen dose was administered at the start of the study period.
For each patient, two coded 100-mL plastic bags containing ropivacaine 1 mg/mL and fentanyl 2 µg/mL, with and without epinephrine 2 µg/mL, were prepared by the hospital pharmacy. At 8:00 AM on the first postoperative day, the epidural infusion was changed, as determined by the randomization procedure, from the triple mixture to one of the two coded epidural mixtures. This was infused at the same rate as the triple epidural mixture for up to 3 h, or for as long as the patient could tolerate any increased pain after receiving the predetermined rescue medication. At this time the epidural infusion was changed back to the ropivacaine-fentanyl-epinephrine mixture, a bolus of 5 mL was given, and the infusion continued at the same rate as before the blinded study period started. The patients were observed for another 5 h for pain intensity and side effects. On the second postoperative day at 8:00 AM, if the patient still had optimal analgesia with the same infusion rate of the ropivacaine-fentanyl-epinephrine epidural mixture, the study was repeated with the alternative, coded epidural mixture.
Whenever the patients were dissatisfied with pain relief, they were allowed to self-administer one 4-mL bolus of the epidural analgesic mixture being infused at the time, up to twice per hour. When pain intensity increased to severe pain when coughing, despite the epidural bolus doses, morphine 1–5 mg was titrated IV by one of the investigators (GN). If pain when coughing remained severe, the epidural infusion was changed back to the unblinded epidural infusion with epinephrine. The amounts of epidural mixture actually administered and any IV morphine were recorded hourly.
Present pain intensity, with the patient resting comfortably in a 10°–15° Fowler position and when coughing, was evaluated hourly by using the VAS. This was a horizontal, ungraded 100-mm line with end points labeled "no pain" and "worst pain imaginable."
Upper and lower sensory levels were determined hourly with an ice cube inside a sterile glove. The area of cold hypoesthesia was mapped on both sides. A score for motor blockade, as described by Bromage (7), was used. Mobilization was evaluated by time out of bed.
Any hypotension, respiratory depression, sedation, nausea and vomiting, pruritus, or urinary retention was noted at hourly intervals during the study. Hypotension was defined as a decrease in systolic arterial blood pressure by 30% from baseline (preoperative value) or to a value <90 mm Hg. Respiratory depression was defined as a respiratory rate less than 10 breaths/min. Sedation and nausea were assessed with a 0–3 score, whereas pruritus and urinary retention were recorded as present or not.
Primary outcome measures were pain intensity at rest and when coughing, evaluated with VAS. A secondary outcome measure was the number of hypoesthetic dermatomal segments. Because of the crossover study design, tests for period effects and treatment interaction (carryover effects) were performed with the Mann-Whitney U-test. For continuous, normally distributed data, comparisons were made by using analysis of variance or paired Student’s t-tests with Bonferroni’s correction if appropriate. VAS scores and sensory blockade were analyzed with Wilcoxon’s signed rank test and the Friedman test for repeated measurements. Categorical data were compared by using 
2 analysis or Fisher’s exact test. Differences referred to as statistically significant corresponded to a two-tailed P value of <0.05. Data are presented as mean ± SD or median with range or interquartile range. The data were analyzed with the SPSS for Windows version 9.0 computer program (SPSS Inc., Chicago, IL).
A pilot study was performed on six patients after major abdominal or thoracic surgery. When epinephrine was removed from the triple epidural mixture, there appeared to be at least a doubling of pain intensity (from 30 to 60 on the 100-mm VAS) during coughing. The SD was approximately one-third of the mean value. Therefore, with = 0.05 and ß = 0.20, it was estimated that at least eight patients would be needed to document a statistically significant increase in pain intensity when coughing (8). We therefore decided to include 12 patients who completed the crossover study.
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Results |
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Four of the 12 patients had severe pain when coughing during infusion of the epidural mixture without epinephrine, despite the rescue analgesic procedures. Therefore, in these patients, the study drug had to be replaced by the epidural mixture with epinephrine 1 h before the blinded 3-h study period was completed. For the analyses of effects, the pain intensity and sensory levels at this time (10:00 AM) were carried forward to 11:00 AM in these four patients.
For pain at rest and when coughing, pain intensity remained low and unchanged during the blinded test period with epinephrine. Figure 2 demonstrates that as soon as after 2 h without epinephrine, there was a highly significant difference in pain intensity from baseline (Friedman test; P < 0.001) and between the periods with and without epinephrine (Wilcoxon’s signed rank test; P < 0.001). This difference increased as long as the mixture without epinephrine was infused. When the epidural infusion was changed back to the mixture with epinephrine, the pain intensity decreased within the next 15 min so that after 1 h there was no difference in pain intensity compared with baseline (Fig. 2).
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2; P < 0.001). There were no episodes of hypotension, bradycardia, or respiratory depression. The heart rate was stable and similar during the periods with and without epinephrine. However, systolic blood pressure and respiratory rate both had a small but statistically significant increase during the period without epinephrine (Table 3, paired Student’s t-test; P < 0.001).
Nausea, which was almost nonexistent during epidural infusion with epinephrine, increased significantly when epinephrine was omitted (Table 3, 2; P < 0.005). It was seen concomitant with increased pain and also after rescue analgesia with IV morphine. Sedation was rare, usually mild, and primarily seen on the first postoperative day. It was similar with and without epinephrine (Table 3). More pronounced sedation was seen only after IV morphine had been given as rescue analgesic medication during epidural infusion of the mixture without epinephrine. Slight pruritus also occurred with equal frequency with or without epinephrine. No patient needed treatment for pruritus.
The urinary bladder catheter was removed in the thoracotomy patients and in one-third of the laparotomy patients during the first postoperative day. At the end of the second postoperative day, two-thirds of all the patients were without a urinary catheter. The remaining patients, all in the Laparotomy group, needed the catheter for various surgical reasons.
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Discussion |
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Epidural vasoconstriction from epinephrine may be the main cause of the observed beneficial effect of epinephrine on the analgesia and side effects of epidural bupivacaine and fentanyl (2). The reduction of epidural blood flow by epinephrine (9) impedes systemic absorption of fentanyl (2,10,11) and local anesthetics (12,13) and reduces their serum concentration (2,10–13). By delaying their removal from the epidural space, epinephrine may increase the amount of fentanyl and local anesthetic drugs reaching the spinal cord and spinal nerve roots, resulting in a more intense and prolonged analgesic effect covering more spinal segments. Unlike bupivacaine, ropivacaine has some intrinsic vasoconstrictive properties (4). Our results may indicate that vasoconstriction caused by epidural epinephrine probably overshadows any vasoconstriction caused by epidural ropivacaine. This agrees with the findings of Hurley et al. (13), who observed a reduced serum concentration of ropivacaine as well as of bupivacaine when epinephrine was added to each of the two local anesthetics and administered epidurally in dogs. When an epidural infusion of epinephrine with a local anesthetic and a lipophilic opioid is discontinued, the increased epidural perfusion increases systemic absorption (10).
The observed increase in nausea when epinephrine was removed may well have been caused by an increased systemic absorption of fentanyl from the epidural space, resulting in more supraspinal opioid side effects (2,10). However, one-third of the patients needed IV morphine during the blinded infusion without epinephrine, which may also have contributed to the nausea. In a recent multicenter study after colonic surgery, the addition of fentanyl 2 µg/mL to ropivacaine 2 mg/mL resulted in decreased infusion rates and enhanced pain control; however, side effects were increased, and readiness to discharge was delayed (14). The hourly consumption of fentanyl (19 µg/h) was approximately the same as in this study, whereas the ropivacaine dose was almost doubled (19 mg/h). With the addition of epinephrine to this mixture, the side effects ascribed to fentanyl and ropivacaine would have been reduced because of a delayed systemic absorption resulting in reduced serum concentrations of the two drugs. At the same time, the ropivacaine concentration could have been reduced to 1 mg/mL, reducing the side effects from the local anesthetic even further.
To document additive analgesic effects and not only increase the side effects, it is necessary to use subanalgesic doses of each of the drugs studied (3,15). Authors who conclude that there are no clinically useful additive effects between epidural fentanyl and ropivacaine (16) or that the combination results in more adverse effects (14) appear to have studied mixtures with too-large doses of fentanyl or ropivacaine. Intuitively, it seems obvious that if almost complete pain relief is achieved by a large dose of one drug, adding another cannot demonstrate any additive effect (15).
It has been known for almost 100 years that epinephrine given into the cerebrospinal fluid causes a profound antinociceptive effect (17). Epinephrine alone (200–1000 µg) injected into the lumbar cerebrospinal fluid caused spinal analgesia sufficient for vaginal delivery, without any clinical signs of spinal cord ischemia even after 1000 µg (18). Epinephrine produces analgesia through an 2-adrenergic mechanism in the substantia gelatinosa of the spinal cord dorsal horn (19,20). When epinephrine 50–100 µg is given alone epidurally, it has a weak hypalgesic effect (21,22). Epinephrine is metabolized by catechol-O-methyl transferase in spinal meningeal cells (23). Therefore, the small dose of epinephrine in our triple epidural analgesic mixture may not reach the spinal cord in a sufficient amount to activate spinal cord 2 receptors. However, even a weak subclinical analgesic effect may cause a significant synergistic effect when combined with drugs causing analgesia by different mechanisms of action (15).
Because epinephrine, fentanyl, and ropivacaine do have separate pharmacodynamic mechanisms of effect in modulation of the nociceptive impulse transmission in the spinal cord, supraadditive analgesic interactions may occur. This has been documented in neurophysiological animal studies with direct spinal cord application of such drugs (3). In the patients in our study, after major thoracic or upper abdominal surgery causing strong postoperative pain, epidural fentanyl 23 µg/h with ropivacaine 11.5 mg/h clearly was subanalgesic, whereas a (12.5%) smaller dose of fentanyl and ropivacaine with epinephrine 20 µg/h resulted in excellent analgesia even during coughing (Fig. 2A). In a dose-finding study of epidural fentanyl plus ropivacaine after major abdominal surgery, it was concluded that at the same infusion rate as in this study, ropivacaine 2 mg/mL with fentanyl 4 µg/mL was the most effective (24). This is double the concentration and dose of both ropivacaine and fentanyl that we need for suppression of dynamic pain after thoracic or upper abdominal surgery when epinephrine 2 µg/mL is added to ropivacaine (or bupivacaine) 1 mg/mL and fentanyl 2 µg/mL. Likewise, in another study after lower abdominal surgery, epidural PCA with ropivacaine 1 mg/mL and fentanyl 2 µg/mL resulted in an increased hourly consumption of ropivacaine and fentanyl compared with this study (25).
Epinephrine 50–100 µg alone in an epidural bolus had only weak but detectable effects (21,22), and epidural infusion of epinephrine alone at 20 µg/h clearly must be insufficient for pain relief after this type of major surgery. Therefore, in addition to the vasoconstrictive pharmacokinetic interaction discussed previously, a supraadditive spinal cord pharmacodynamic analgesic interaction may be present among epinephrine, fentanyl, and ropivacaine in this epidural analgesic mixture.
Potent constrictive action of epinephrine on vessels outside the central nervous system has led to concern by some that the blood supply of the spinal cord could suffer. However, there are no human data supporting this concern. Epinephrine in bolus doses of 100–200 µg has been used with spinal anesthetics for decades without any ill effects on spinal cord function being observed (26,27). Recently Vaghadia et al. (28) documented that spinal cord functions (spinothalamic, dorsal column, and motor) were well preserved in patients during spinal anesthesia with lidocaine 10 mg and sufentanil 10 µg, with and without epinephrine 50 µg. Animal studies have shown that up to 200 µg of subarachnoid epinephrine does not decrease spinal cord blood flow in cats or dogs (9,29,30). A study in dogs using a spinal-window preparation demonstrated a small reduction in spinal pial vessel diameter produced by epinephrine 5 µg/mL (31). Although it has been documented that subarachnoid epinephrine may increase the neurotoxic effects of subarachnoid lidocaine and tetracaine in rats, they could not ascribe this to a decreased spinal cord blood flow or to epinephrine alone (32,33). In patients, the dose and concentration of epidural epinephrine that we used do not have detrimental effects on spinal cord blood flow.
Because the side effects are different for each of the three components in the epidural mixture, reducing the dose needed of each component to maintain the analgesic effect also reduces the total load of dose-dependent side effects (1,2,34). In this study, with a very small incidence of side effects during infusion of the epinephrine-containing mixture, there was a significant increase in the occurrence of nausea in the period without epinephrine, although this may in part have been caused by the IV morphine needed for rescue analgesia. We also demonstrated that more patients were mobilized out of bed during the period with epinephrine, most likely because of better pain relief and less nausea and therefore greater ease of mobilization during the period with epinephrine added to epidural ropivacaine and fentanyl.
In conclusion, this prospective, randomized, double-blinded, crossover study of thoracic epidural infusion of approximately 10 mg of ropivacaine and 20 µg of fentanyl, with or without 20 µg of epinephrine, per hour demonstrated that epinephrine markedly improved the pain-relieving effect and increased the sensory blockade of ropivacaine and fentanyl. Nausea was reduced, and mobilization of the patients was facilitated.
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Acknowledgments |
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We are grateful to the Hospital Pharmacy, Rikshospitalet University Hospital, Oslo, Norway, for preparing the study drugs and to Audun Stubhaug, Department of Anesthesiology, Rikshospitalet University Hospital, for randomizing and blinding the study drugs.
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Footnotes |
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