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Departments of *Anesthesiology and
Colon and Rectal Surgery, Tri-Service General Hospital and National Defense Medical Center, National Defense University, Taipei, Taiwan, Republic of China; and
Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina
Address correspondence and reprint requests to Ching-Tang Wu, MD, Department of Anesthesiology, Tri-Service General Hospital, National Defense Medical Center, National Defense University, #325, Section 2, Chenggung Rd., Neihu 114, Taipei, Taiwan, Republic of China. Address e-mail to wuchingtang{at}msn.com
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Abstract |
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) and antiinflammatory (IL-1 receptor antagonist (RA)) cytokines in patients who underwent elective colorectal surgery and that they would provide better postoperative analgesia. Forty patients were randomly assigned to 1 of 2 groups of 20 each: the control group received normal saline 10 mL, whereas the clonidine group received epidural clonidine 150 µg diluted with 9 mL of normal saline 30 min before surgery. Venous blood samples for cytokine levels were obtained before induction, at the end of surgery, and after surgery at 12 and 24 h. After surgery, the clonidine group patients received PCEA with morphine (0.1 mg/mL) and clonidine (1.5 µg/mL) in 0.2% ropivacaine 100 mL, whereas control group patients received only PCEA morphine and ropivacaine. Patients in the clonidine group exhibited longer PCEA trigger times, lower pain scores at rest and while coughing, less morphine consumption, and a faster return of bowel function throughout the 72-h postoperative observation period, compared with patients in the control group. For patients in the clonidine group, production of IL-1RA, IL-6, and IL-8 was significantly less increased at the end of the surgical procedure and at 12 and 24 h after surgery. However, the concentrations of IL-1ß and TNF- were not significantly increased. IMPLICATIONS: The combination of preoperative epidural clonidine with postoperative patient-controlled analgesia morphine, ropivacaine, and clonidine provides preemptive analgesia and results in reduced pain intensity, diminished opioid consumption, a faster return of bowel function, and attenuated production of interleukin (IL)-6, IL-8, and IL-1 receptor antagonist (RA) in the perioperative period, without any complications. The lower levels of IL-6, IL-8, and IL-1RA could diminish pain transmission and central nervous system sensitization, thus improving postoperative pain and allowing a faster return of bowel function.
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Introduction |
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Clonidine can be used for premedication because it modulates hemodynamic changes during anesthetic induction, as well as during and after surgery; reduces the incidence of myocardial ischemia during surgery; and decreases major anesthetic requirements for volatile anesthetics and opioids during surgery (3). It also benefits in postoperative pain management, especially when administered epidurally or intrathecally (4,5). Moreover, clonidine provided better pain management when combined with opioids (6–8), with or without local anesthetics, and was stable and compatible with these drugs (8).
Interleukin (IL)-6 is a main proinflammatory cytokine that correlates with the severity of surgery and the magnitude of the tissue injury (9). It can lead to hyperalgesia (10). IL-1ß, tumor necrosis factor (TNF)-, and IL-8 can induce central sensitization (11). These proinflammatory cytokines could modulate pain indirectly by altering pain transmission via cytokine-induced release of neuroactive substances such as nitric oxide (NO), oxygen free radicals, prostaglandins, and excitatory amino acids from microglia and astrocytes. These substances could be the proximate cause for the pain-enhancing effects of proinflammatory cytokines (12). In contrast, IL-1 receptor antagonists (RAs) act as "functional antagonists" by inhibiting the production of proinflammatory cytokines to reduce the inflammatory response (12).
Colorectal surgery is associated with higher levels of IL-6 than any other operation (9) and is frequently associated with postoperative ileus. Moreover, the use of large amounts of opioids to relieve postoperative pain might lead to the development of postoperative ileus. Upregulation of proinflammatory cytokines has been shown to contribute to postoperative ileus (13). Therefore, we investigated the effect of preoperative epidural and postoperative patient-controlled epidural analgesia (PCEA) clonidine on the responses of cytokines IL-1ß, TNF-, IL-6, IL-8, and IL-1RA during the perioperative period. We also examined the preemptive analgesic effect of epidural clonidine on postoperative pain and bowel function.
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General anesthesia was induced with fentanyl (2 µg/kg), atracurium (5 mg), thiopental (3–5 mg/kg), and lidocaine (1.5 mg/kg) by IV administration, and tracheal intubation was facilitated with succinylcholine (1.5 mg/kg). Anesthesia was maintained with desflurane in oxygen (300 mL/min) via a total closed-circuit system. The end-tidal desflurane concentration was controlled to maintain the systolic blood pressure within the range of 20% of the basal systolic pressure. Respiratory frequency and tidal volume were adjusted to maintain the end-tidal carbon dioxide level at 35 mm Hg. Esophageal temperature was maintained at 35°C–37°C. All patients received balanced salt solution at a rate of 6 mL · kg–1 · h–1 perioperatively and 2 mL · kg–1 · h–1 postoperatively. Patients likely to receive blood transfusions during the perioperative period were not included in this study. No additional opioids were given during the operation. At the end of surgery, residual neuromuscular block was antagonized with edrophonium (0.8 mg/kg) and atropine (0.01 mg/kg), and the endotracheal tube was removed when the patient started to breathe spontaneously.
On arrival at the postanesthesia care unit, patients were connected to the PCEA pump and received 10 mL of PCEA solution at the first trigger and then 4 mL per delivery (lockout time was 15 min without a 4-h limitation or continuous background infusion). The clonidine group received PCEA with morphine (0.1 mg/mL) and clonidine (1.5 µg/mL) in 0.2% ropivacaine 100 mL, whereas the control group received only PCEA morphine and ropivacaine. A 10-cm VAS (with end-points labeled "no pain" and "worst possible pain") was used to assess pain intensity at rest and after coughing at 1, 2, 4, 12, 24, 48, and 72 h after the completion of surgery.
We recorded the time to first PCEA trigger (the patient’s first use of analgesic), total PCEA trigger and delivery times, the time to the first passage of flatus, and side effects related to morphine (drowsiness, dizziness, nausea, and vomiting) and clonidine (hypotension, bradycardia, sedation, and motor block) for 72 h after the operation. All observations were made by a double-blinded study nurse. Side effects were treated as necessary.
Blood samples were obtained 10 min before the clonidine infusion, at the end of surgery, and after surgery at 12 and 24 h. Sampled blood was collected into EDTA tubes and centrifuged at 3000 rpm for 10 min at 4°C immediately after sampling. Thereafter, plasma was stored at –70°C until all the samples were collected. Plasma concentrations of TNF-, IL-6, IL-8, IL-1ß, and IL-1RA were measured with commercial quantitative sandwich enzyme-linked immunosorbent assay kits (Quantikine; R & D Systems, Minneapolis, MN). The sensitivity of the assay for IL-6, IL-1ß, IL-8, TNF-, and IL-1RA was 0.7, 0.3, 4.4, 0.5, and 22 pg/mL, respectively. Standards were prepared, and the appropriate volume of sample or standard was added to a 96-well polystyrene microtiter plate precoated with monoclonal antibody to the appropriate cytokine or RA. All samples and standards were run in duplicate. The plate was incubated for the recommended time. Each well was then aspirated, and the plates were washed with the buffered surfactant provided. An enzyme-linked polyclonal antibody against the cytokine or RA was then added, and again the plates were incubated and washed. Substrate solution was added to each well, and the optical density was read at the appropriate wavelength for each assay period. All values are reported as picograms per milliliter. The intraassay and interassay coefficients of variation of the immunoassay kits ranged between 5% and 10%. Cross-reactivity with other factors was negligible in all cytokine assays.
Parametric values were analyzed by using Student’s t-test. Data were analyzed for each measure by using analysis of variance with repeated measures, and the Bonferroni procedure was conducted as appropriate, correcting for multiple comparisons. Side effects were analyzed by using the 
2 test. Probability values of P < 0.05 were considered significant. The results are expressed as mean ± SD.
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in the clonidine group were 3.6 ± 1.2 pg/mL, 3.3 ± 1.0 pg/mL, 3.6 ± 1.0 pg/mL, and 3.3 ± 0.9 pg/mL before surgery, at the end of the surgical procedure, and 12 and 24 h after surgery, respectively. The control group values were 3.6 ± 1.2 pg/mL, 3.7 ± 1.0 pg/mL, 3.9 ± 0.9 pg/mL, and 3.4 ± 1.1 pg/mL, respectively. The levels of IL-1ß in the clonidine group were 2.0 ± 0.4 pg/mL, 2.1 ± 0.4 pg/mL, 1.9 ± 0.3 pg/mL, and 1.9 ± 0.3 pg/mL before surgery, at the end of the surgical procedure, and 12 and 24 h after surgery, respectively. The control group values were 2.0 ± 0.4 pg/mL, 2.0 ± 0.4 pg/mL, 1.9 ± 0.3 pg/mL, and 1.9 ± 0.3 pg/mL, respectively. The levels of TNF- and IL-1ß exhibited no change over time and were not different between the clonidine and control groups. Although arterial blood pressure (BP) and heart rate (HR) were lower in the clonidine group than the control group, they did not reach a significant difference (Table 1). This might be because BP was controlled by the dosage of desflurane. This is confirmed by the fact that the end-tidal concentration of desflurane was smaller in the clonidine group (Table 1). Because epidural clonidine 150 µg was injected during general anesthesia, we could not detect motor block or sedation. The clonidine group received small doses of clonidine (mean, 78.6 µg) for 3 days after surgery, and no patient experienced motor block or sedation. Furthermore, there was no significant difference between groups in wound infection, tumor recurrence, or metastatic rate during the 6-mo follow-up period (Table 3).
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Discussion |
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Surgery-associated tissue injury sets off a cascade of related events, including nociception and inflammatory reactions. Tissue and peripheral nerve injury leads to local inflammatory reaction, which is accompanied by increased levels of proinflammatory cytokines (10). Because of the feedback cascade between nociception and proinflammatory cytokines, it is also possible that pain contributes to higher levels of proinflammatory cytokines. Meanwhile, the antiinflammatory cytokine levels also increased, tending to maintain balance and hemostasis. These proinflammatory cytokines can induce peripheral and central nerve system sensitization and lead to hyperalgesia (10).
IL-6 is a main proinflammatory cytokine that is produced as early as two to four hours after tissue damage (17), and it is the primary stimulus for the acute-phase response. Tissue injury elicited by trauma or surgery brings about immediate and well localized pain, after which pain is sustained. IL-6 is produced in substantial quantities at the site of a surgical wound (18) and then enters the systemic circulation, where its concentration correlates with the severity of surgery (9) and the magnitude of tissue injury. By 24 to 36 hours after surgery, the levels of IL-6 in the plasma decrease to preoperative values because of attenuated production. Moreover, IL-6 can induce peripheral and central nervous system sensitization, leading to hyperalgesia (10). This study demonstrated that IL-6 was reduced at the end of surgery and 12 hours after surgery and that it returned to baseline at 24 hours after surgery. Marz et al. (19) reported that the sympathetic nervous system can produce IL-6 and may respond to it in an autocrine/paracrine manner. Moreover, Dorman et al. (20) reported that clonidine influenced IL-6 levels in patients undergoing upper abdominal surgery via attenuated adenyl cyclase activity and then by a reduced cyclic adenosine monophosphate level.
IL-1ß can induce central sensitization via IL-1 receptors (11). Sachs et al. (21) concluded that IL-1ß induced persistent mechanical nociceptor hypersensitivity as a result of the endogenous release of eicosanoids. In addition, IL-1ß contributes to pain mechanisms and hyperalgesia in several ways, including upregulation of cyclooxygenase-2 receptors (22) and increased production of substance P (23), nerve grow factor (24), glutamine, and NO synthase (25). Unfortunately, we were not able to demonstrate the response of clonidine to IL-1ß concentrations. Similarly, IL-1ß is not readily released into the systemic circulation, and its plasma levels may be very low even if inflammation is severe (26,27).
We demonstrated a significant difference in the levels of IL-1RA. IL-1RA is a naturally competitive inhibitor of IL-1ß and competes with IL-1ß for the binding of its cell-surface receptors on effector cells. Therefore, IL-1RA has often been assumed to provide a marker for the presence of IL-1ß (26,27). IL-1RA was released with IL-1ß, signaling the acute-phase response and correlating well with the grade of inflammation (28). In addition, Cunha et al. (29) demonstrated that IL-1RA was released at the sites of inflammation and that it limited inflammatory hyperalgesia. It acts as a functional antagonist by inhibiting the production of proinflammatory cytokines to reduce the inflammatory response, antagonizing substance P release, and providing an analgesic effect (12). To achieve immune homeostasis, the control group experienced more postoperative pain and thus higher levels of IL-1RA to antagonize substance P release and provide an analgesic effect.
TNF--induced mechanical nociceptor hypersensitivity results from the concomitant endogenous release of eicosanoids and sympathomimetic mediators (21). Several studies have reported significant postoperative TNF- levels measured in wound and peritoneal fluids; however, perioperative circulatory TNF- changes were undetectable (30). These findings were consistent with this study’s findings, because TNF- did not change over time and was not different between groups. However, it is still conceivable that the levels of TNF- in the area of tissue injury were higher than those in the plasma, leading to a local effect on cytokine-producing cells (31).
Local tissue injury, resulting in the release of cytokines, may play a role in upregulating sympathetic tone. It has been well demonstrated that epidurally administered clonidine results in a decrease in both central adrenergic and peripheral sympathetic outflow (32). IL-8 is the first endogenous mediator to be identified as evoking hyperalgesia that involves the sympathetic nervous system. Because IL-8 is released by activated macrophages and endothelial cells, it may be a humoral link between tissue injury and sympathetic hyperalgesia (33). Meanwhile, epidural clonidine markedly reduces immune cell recirculation and the inflammatory cascade among the blood, lymphoid organs, and extralymphoid tissues, primarily by its spinal sympathetic effect (4). Moreover, Sachs et al. (21) found that IL-8 induced persistent mechanical nociceptor hypersensitivity via sympathetic amines. Our results were consistent with their reports, showing that epidural clonidine suppresses the perioperative levels of IL-8 and provides more effective pain relief.
Postoperative ileus is defined as a disruption of the normal peristaltic motion of the gut; it results in failure to propel intestinal contents through the gastrointestinal tract. It lasts from 72 to 96 hours and is due mostly to the inhibition of extrinsic motility regulation in the colon (34). The most commonly accepted pathophysiologic feature of postoperative ileus is that abdominal pain activates a spinal reflex arc that inhibits intestinal motility. In addition, surgical stress induces sympathetic hyperactivity, and excessive sympathetic stimulation of the bowel inhibits organized propulsive activity. Thus, both nociceptive afferent and sympathetic efferent nerves are believed to be key initiators of ileus (35). Recently, the upregulation and release of proinflammatory cytokines after surgery was demonstrated to contribute to postoperative ileus (13). Therefore, the finding that the clonidine group exhibited faster recovery of bowel function might have been due to the multiple effects of epidural clonidine—attenuation of sympathetic outflow, cytokine production, a synergic effect with morphine and ropivacaine, and a local anesthetic effect—thus reducing postoperative pain and diminishing morphine consumption.
Although bowel function was restored significantly earlier in the clonidine group, discharge from the hospital was similar for both groups. It is interesting to note the reason that patients who had faster recovery of bowel function were kept in the hospital even though they were ready to be discharged home. The most obvious reasons were social: patients were not expecting to go home until removal of the stitches, and the surgeon was cautious with early discharge.
A limitation of our study was that we measured cytokines only over a 24-hour postoperative period. The cytokine levels were still higher than baseline at the end of our measurement period but should have decayed approximately 24–36 hours after surgery (9). Another limitation is that the total leukocyte, neutrophil, and lymphocyte counts and the concentration of stress hormones were not measured in this study. However, Novak-Jankovic et al. (4) reported that epidural clonidine can modulate the immune stress response and attenuate immune cell counts. In addition, we did not measure the dose response of clonidine in PCEA solution, but we believe that the study dose was similar to those typical in clinical practice.
In conclusion, the combination of preoperative epidural clonidine with postoperative PCEA morphine, ropivacaine, and clonidine provides preemptive analgesia and results in reduced pain intensity, diminished opioid consumption, a faster return of bowel function, and attenuated production of IL-6, IL-8, and IL-1RA in the perioperative period. Meanwhile, this immune-modulatory effect did not increase wound infection, tumor recurrence, or metastatic rates, although the cases were few and illnesses not severe.
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