Effect of Preemptive Epidural Analgesia on Cytokine Response and Postoperative Pain in Laparoscopic Radical Hysterectomy for Cervical Cancer
Posted on: Friday, 9 May 2008, 03:00 CDT
By Hong, Jeong-Yeon Lim, Kyung T
Background and Objective: Surgical stress and general anesthesia suppress immune function. Preemptive epidural analgesia can affect the perioperative immune responses, and influence cancer management. Methods: Forty women undergoing elective laparoscopic radical hysterectomy for cervical cancer were allocated to this prospective, randomized, double-blind trial. Before inducing anesthesia, 2 mg morphine dissolved in 15 mL of 1 % lidocaine (preemptive group) or the same volume of normal saline (control group) was administered into the epidural space through a prepared catheter in a double- blind manner, using sealed syringes. After peritoneal closure, the other drugs in the remaining sealed syringe were administered in the reverse manner. All patients were then administered lidocaine plus morphine over a 72-hour period, using a patient-controlled epidural analgesia pump.
Results: The interleukin-6 levels in both groups increased significantly after surgery. These elevations were significantly less pronounced in the preemptive group than in the control group. The interleukin-2 level in both groups decreased significantly after surgery. Seventy-two hours after surgery, the interleukin-2 level returned to its baseline value in the preemptive group but not in the control group. The number of lymphocytes in both groups decreased significantly after surgery. The pain scores at 6 and 12 hours after surgery in the preemptive group were significantly lower than in the control group.
Conclusions: Preemptive epidural analgesia is a reasonable approach for potentially controlling perioperative immune function and preventing postoperative pain in patients undergoing cancer surgery. Reg Anesth Pain Med 2008;33:44-51.
Key Words: Cervical cancer. Cytokine, Laparoscopy, Preemptive epidural analgesia.
There has been increasing interest in postoperative compromised immune function, as caused by tissue damage, anesthesia, postoperative pain, and psychological stress. This interest has extended to immune function and its potential effects on cancer management. Indeed, a compromised defense mechanism affects a metastasis disseminated at surgery, and augments the growth of residual cancer in animal models.1,2 Thus, adjuvant modalities that preserve or enhance immune function in the perioperative period may improve the overall outcome of cancer patients.
The importance of peripheral and central modulation of nociception has fostered the concept of "preemptive analgesia" in patients undergoing surgery. This type of management pharmacologically induces an effective analgesic state prior to surgical trauma. Experimental evidence suggests that preemptive analgesia can effectively attenuate peripheral and central sensitization to pain. Several reports documented the positive effects of preemptive analgesia on postoperative immune function and metastatic progression after major surgery.3-7 In addition, because pain not only results in suffering, but is also an important cause capable of facilitating the progression of metastatic disease,8 a preemptive epidural blockade may result in effective postoperative analgesia, and may improve the results of certain cancer surgeries.9,10
The mechanisms of preemptive neuraxial blockade on the postoperative immune function of cervical cancer patients are largely unknown. Interleukin (IL)-6 is a main proinflammatory cytokine that correlates with the severity of surgery and the magnitude of tissue injury. Interleukin-2 also plays critical roles in the immunoregulation of metastatic disease, and is essential for the development of T-cell responses. Thus, both IL-6 and IL-2 play a central role in the development and maintenance of the major immune response to cancer surgery.
In search of an effective immunologic modulation of preemptive analgesia, we measured immune responses in cancer patients undergoing surgery. Our hypothesis was that differences in immune response would occur when preemptive epidural analgesia with opioid and local anesthetics was provided during cancer surgery. We also expected that hemodynamic stability would result from sympathetic blocks during laparoscopic surgery. Our study investigated the effects of preemptive epidural analgesia on perioperative IL-2 and IL-6 cytokine responses and white blood cell counts in patients with cervical cancer who underwent laparoscopic radical hysterectomy. Intraoperative hemodynamics and postoperative pain were also compared.
Methods
Patients
After obtaining approval from the Hospital Institutional Review Board as well as written, informed consent from the patients, 40 women (American Society of Anesthesiologists physical status I or II) undergoing elective laparoscopic radical hysterectomies for cervical cancer (International Federation of Gynecology and Obstetrics stage Ib) were enrolled in our prospective randomized trial. The exclusion criteria involved a previous history of chronic pain or opioid use, an infectious condition, psychiatric problems receiving psychoactive medication, or any contraindications to epidural analgesia.
Anesthesia and Pain Management
The day before surgery, the patients were trained to complete a visual analog scale (VAS) for pain, and to use a patient-controlled epidural analgesia (PCEA) device (ANAPA, Ewha, Siheung, South Korea). Patients were premedicated with atropine 0.5 mg and midazolam 3 mg intramuscularly, 1 hour before surgery. Fifteen minutes before the induction of anesthesia, an epidural catheter (18- G epidural minipack, SIMS Portex, Hythe, United Kingdom) was inserted between the L2 and L3 or Ll and L2 interspaces, using a midline approach, and was advanced 5 to 7 cm cephalad. The position of the epidural catheter was tested with 3 mL of 2% lidocaine. Patients were randomly allocated into two groups, according to a computer-generated table of random number assignments. Patients and data collectors were double-blinded to the treatment regimen. Based on the randomized sequence, the nursing staff prepared two bolus syringes: one filled with 2 mg morphine dissolved in 15 mL of 1% lidocaine, and the other filled with the same volume of preservative- free normal saline. The nursing staff also filled the syringes with 1% lidocaine for infusions during the surgeries of patients in the preemptive group (n = 20), and with normal saline for patients in the control group (n = 20). Syringes were sealed and then transferred to an anesthesiologist blinded to their contents.
General anesthesia was induced using intravenous 1 [mu]g/kg fentanyl, 2 mg/kg propofol, and 0.5 mg/kg rocuronium. After inducing anesthesia, an anesthesiologist blinded to the contents of the syringes injected into the epidural space either 2 mg morphine, as dissolved in 15 mL of 1% lidocaine (preemptive group), or 15 mL of normal saline (control group). This injection was followed by an epidural infusion of 1% lidocaine (5 mL/h) to patients in the preemptive group, and normal saline to patients in the control group, until peritoneal closure.
During surgery, intravenous remifentanil was administered to the patients by target-controlled infusion, set at a target concentration of 1 to 3 ng/mL to obtain proper analgesia. The concentration of remifentanil was titrated to achieve adequate anesthesia against noxious surgical stimuli. Rocuronium 10 mg/h was also infused to the patients for muscle relaxation. The sevoflurane concentration was controlled to maintain a systolic blood pressure within a 20% range of basal systolic pressure. Respiratory frequency and tidal volume were adjusted to maintain an end-tidal CO2 level of 35 mm Hg. The esophageal temperature was maintained at 35[degrees]C to 37[degrees]C.
After peritoneal closure, 15 mL of 1% lidocaine mixed with 2 mg morphine was administered to patients in the control group. The same volume of normal saline was administered to patients in the preemptive group, using the remaining sealed syringe. All patients were then attached to a PCEA pump and received 2 mL lidocaine (1%) plus 0.2 mg/mL morphine per demand (lockout time, 15 minutes), with a continuous background infusion of 2 mL/h for 72 hours postoperatively.
At the end of surgery, residual neuromuscular blockade was antagonized with neostigmine and atropine, and the endotracheal tube was removed when the patient began to breathe spontaneously.
Measurements
Blood pressure and heart rate were measured before the induction of anesthesia, and these findings were used as baseline values. Blood pressure and heart rate were then measured at 5-minute intervals during surgery. A pneumoperitoneum was created in the Trendelenburg position with a Veress needle, using a CO2- insufflator (OP-PNEU Electronic Semm System, WISAP, Saverlach, Germany), and intraabdominal pressure (IAP) was maintained automatically at 12 mm Hg. Hypotension, defined as a decrease of systolic blood pressure >20% of baseline value, was treated with an infusion of Ringer's lactate solution and an incremental dose of ephedrine. A 10-point VAS at rest (with endpoints labeled "no pain" and "worst possible pain") was used to assess pain intensity at 1, 3, 6, 12, 24, 48, and 72 hours after surgery. The postoperative side effects and treatments were observed. All data were collected in a blinded manner by an anesthesiologist who was unaware of the analgesic method used. Venous blood samples were collected four times throughout the study period (30 minutes before induction, immediately after surgery, and 24 and 72 hours postoperatively). The changes in white cell count and compositions immediately after surgery, on postoperative day 1, and on postoperative day 3 were compared with baseline values within the groups. These values from the two groups were then compared. Hematologic measurements were performed using an Advia 120 (Bayer Co., Dublin, Ireland).
To determine cytokine levels, blood samples were collected into a plain vacuum tube and transported immediately to the laboratory on ice. Samples were centrifuged, and the serum was removed and stored at -20[degrees]C until analysis. Cytokine concentrations were determined through an enzyme immunoassay method, using commercially available kits for IL-2 and IL-6, according to the manufacturer's instructions (R & D Systems, Inc., Minneapolis, MN). The intra- assay and interassay precisions for IL-6 were 0.430 (pg/mL) +- 0.03 (SD) and 0.452 (pg/mL) +- 0.08 (SD), respectively. The intra-assay and interassay precisions for IL-2 were 96.8 (pg/mL) +-4.1 (SD) and 245 (pg/mL) +-11.7 (SD), respectively.
Table 1. Patient Characteristics and Clinical Variables
Statistical Analysis
A power analysis was performed on the results of a preliminary study to determine the sufficient sample sizes. The prestudy power analysis indicated that a sample size of 37 subjects would be required to detect a 30% difference of IL-6 and IL-2 between the groups with a = 0.05 and beta = 0.1 and a standard deviation of 30% in this population. We enrolled 20 patients in each group to allow room for protocol violations.
Statistical analyses were performed using a statistical software package (SPSS/PC+, SPSS, Inc., Chicago, IL). Data were analyzed by analysis of variance (ANOVA) with repeated measures, using one dependent variable on the time course. The differences between the two groups were evaluated using the Student t test, Mann-Whitney rank sum test, and Fisher exact test, where appropriate. P < 0.05 was considered significant.
Results
The demographic data and operative procedures of the two groups were similar (Table 1 ). None of the patients required a blood transfusion during or after surgery. All patients underwent insertion of epidural catheters, and all catheters were functional.
Intraoperative changes in the heart rates of the two groups were similar during surgery. Twenty minutes, 80 minutes, and 90 minutes after anesthesia, the systolic blood pressure in the preemptive group was significantly lower than in the control group (Fig 1).
Fig 1. Hemodynamic changes during surgery. During 60-minute period after anesthesia, blood pressures in the control group were significantly higher than in the preemptive group. Intraoperative changes in heart rates in the two groups were similar during surgery. *P < .05 compared with control group. [dagger]P < .05 compared with baseline value.
Repeated-measures ANOVA on the IL-6 levels in both groups revealed significant increases in IL-6 after anesthesia and surgery (Table 2). After surgery, the IL-6 levels in the preemptive group were significantly lower than in the control group. However, IL-2 levels decreased significantly after surgery compared with baseline values in both groups. Twenty-four hours after surgery, the IL-2 levels were significantly lower in the preemptive group than in the control group.
The numbers of leukocytes and neutrophils in the two groups increased significantly after surgery compared with baseline values (Table 3). The numbers of lymphocytes in both groups decreased significantly after surgery, and were low until postoperative day 1 in the control group. The total number of circulating leukocytes, monocytes, and neutrophils between groups was similar before the induction of anesthesia and after surgery.
The pain scores at 6 and 12 hours after surgery in the preemptive group were significantly lower than in the control group (Fig 2). The total dose (mg) of morphine administered via PCEA during the post-operative 48 hours was significantly lower in the preemptive group than in the control group 21.7 +- 8.7 mg vs. (29.2 +- 10.1 mg, mean +- SD).
Table 4 lists postoperative side effects. The incidences of nausea and vomiting were significantly higher in the control group than in the preemptive group. The incidence of pruritus was significantly higher in the preemptive group than in the control group.
Table 2. Changes in Interleukin-6 and Interleukin-2 Levels
Discussion
These results show that the level of IL-6 production was high in all patients after surgery, and that such elevations were significantly less pronounced in the preemptive group than in the control group. The level of IL-2 production decreased significantly after surgery in both groups, but IL-2 levels in the preemptive group returned to normal 72 hours after surgery, whereas those in the control group did not. In addition, patients in the preemptive group experienced less severe postoperative pain, whereas those in the control group reported higher VAS scores. These findings may be related to the preemptive effects of local anesthetics and opioids, and are in accordance with clinical reports of alterations in cytokine levels after surgery.7,10
Earlier reports indicated that morphine suppressed the lymphocyte proliferative response to mitogens when administered systemically, but not when given intrathecally.11-13 However, Beilin et al.7 reported that preemptive epidural bupivacaine and fentanyl were associated with an attenuated production of proinflammatory cytokines (IL-1 and IL-6), and with decreased suppression of anti- inflammatory cytokines (IL-2) after gynecologic noncancer surgery. Akural et al.10 reported that preemptive epidural sufentanil treatment had minor effects on the immune depressive response after abdominal hysterectomy. Thus, opioids have multiple effects on the immune response via the central nervous system and direct effects on the immune system. Interleukin-6 is one of the key cytokines in anesthesia and surgery. Interleukin-6 is produced early after tissue damage, and is the main proinflammatory cytokine responsible for inducing the systemic changes known as the acute-phase response.14,15 This cytokine can induce the peripheral and central nervous system sensitization that leads to pain augmentation.16 Many researchers reported that IL-6 levels are elevated after nerve injury, both peripherally and centrally, thus contributing to hyperalgesia by direct spinal nociceptive mechanisms or by glial activation in animal studies.17,18
Table 3. Total Number of Circulating Leukocytes and Percentage of Lymphocytes, Monocytes, or Neutrophils Before Induction of Anesthesia (Baseline) and 2 Hours, 1 Day, and 3 Days After Surgery
Fig. 2. Postoperative pain scores. Visual analog pain scores at 3, 6, and 12 hours after surgery in the preemptive group were significantly lower than in the control group. Data are given in a box-plot with interquartile ranges, medians (solid lines), and means (bold lines). *P < .05 compared with the control group.
Interleukin-2, which is an anti-inflammatory cytokine released from the lymphocytes after IL-1 stimulation, causes the rapid proliferation of effector cells, and is decreased after major surgery.19,20 The severity of injury and depressed IL-2 production are correlated. Interleukin-2 is also an important cytokine produced by activated CD4+ lymphocytes, and plays critical roles in various immunologic cancer phenomena.21,22 Interleukin-6 stimulated the proliferation and differentiation of T-cells and B-cells, enhanced antibody secretion, increased natural killer (NK) cell activity and quantity, and activated lymphokine-activated killer (LAK) cells.23,24 The NK cells are believed to play an important role in host defenses against certain cancers. The LAK cells are also broadly cytotoxic tumor cells. The main functional roles of IL-2 pertain to the development and maintenance of cytotoxic responses by NK cells and cytotoxic T lymphocytes, which are especially expressed in cancers. Thus these cytokines (IL-6 and IL-2) were chosen for the present study.
Our findings may also be examined in relation to the level of postoperative pain experienced by patients. In the present study, patients in the preemptive group received additional analgesia (lidocaine 1% infused via the epidural catheter until peritoneal closure), whereas the control group received saline. Thus, patients in the preemptive group were exposed to more intraoperative analgesia and antinociception. Furthermore, intraoperative sevoflurane was administered more heavily in the control group, which may have also partly affected the results. It was suggested that nociception and proinflammatory cytokines play a mutual up- regulatory role.25 Hence, the increased production of proinflammatory cytokines might contribute to more severe pain and vice versa. Because of the feedback cascade between nociception and proinflammatory cytokines, the experience of pain possibly contributes to higher levels of proinflammatory cytokines. Peripheral nerve injury activates glia cells, which in turn increase the production of proinflammatory cytokines in the central nervous system. This may be related to the observation that patients in the preemptive group experienced less postoperative pain and exhibited reduced production of proinflammatory cytokines.
Other drugs that are administered to surgical patients can affect the immune function in many ways.26,27 In their animal study, Melamed et al.26 reported on the suppression of NK cell activity and the promotion of tumor metastasis by ketamine, thiopental, and halothane, but not by propofol. Colacchio et al.27 reported that ketorolac may be an effective agent for restoring perioperative immune competence, whereas the use of continuous morphine might have significant deleterious effects. Therefore, non-narcotic pharmacologic options are recommended for the control of postoperative pain, particularly with the use of epidural analgesia and the parenteral administration of nonsteroidal antiinflammatory drugs, which would avoid narcoticinduced immune depression. In other recent studies,7,10,28 patients receiving preemptive epidural opioids or a mixture of local anesthetics and opioids exhibited reduced suppression of lymphocyte proliferation and an attenuated proinflammatory cytokine response in the postoperative period. These findings are partially consistent with our results. Several studies of animals and humans showed that opioids can exert immunosuppressive effects.29-31 Consistent with these observations, opioid administration was associated in animals with increased susceptibility to bacterial and viral infections,32 and with decreased survival in tumor-bearing animals.33 On the other hand, opiate-induced analgesia in the perioperative period attenuated the metastatic-enhancing effects of surgery in rats.34 Hence, opiates can modulate host-defense mechanisms and can either enhance or attenuate tumor metastases. Because the independent effects of preemptive opioids on human immune function are largely unknown, their mechanisms and clinical importance require further study.
Table 4. Postoperative Side Effects
Although we did not find conclusive data to support the hypothesis that a reversal of perioperative immune defects in cancer patients would improve their survival, we observed some therapeutic effects on the improvement of immune function in our human trial. Larger, more elaborate, multicenter long-term follow-up studies are needed to address this hypothesis in the future.
Although we designed this study to be double-blinded, we acknowledge a potential limitation. The observer could possibly identify patients receiving a bolus of 1% lidocaine based on reductions in blood pressure because of sympatholysis and failure to produce hypertension after surgical incision. Indeed, Figure 1 illustrates these expected changes in blood pressure. However, intraoperative hypotension management was controlled by the study protocol. Therefore, we do not think that this possible bias should have influenced the perioperative results. Postoperative data collection, including pain scoring, postoperative management, and blood sampling, was performed by another anesthesiologist who was blind to the study drug.
An effective restimulation of the immunosuppression that had been produced by a major operation and anesthesia for cancer was our goal. We conclude that preemptive epidural analgesia using morphine and lidocaine can be a reasonable approach for potentially controlling perioperative immune function and preventing postoperative pain in cancer patients undergoing surgery. We also speculate that preemptive epidural analgesia may affect long-term survival by modulating the immune response for tumor-cell implantation, but this requires further study.
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Jeong-Yeon Hong, M.D., and Kyung T. Lim, M.D.
From the Department of Anesthesiology and Pain Medicine (J.Y.H.), Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, and Department of Obstetrics and Gynecology (K.T.L.), Cheil General Hospital and Women's Health Center, Kwandong University College of Medicine, Seoul, Korea.
Accepted for publication July 13, 2007.
Reprint requests: Jeong-Yeon Hong, M.D., Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Severance Hospital, 134 Sinchon-dong, Seodaemun-gu, Seoul 120-752, South Korea. E-mail: jenyhongg@hanmail.net mailto:jenyhongg@hanmail.net (c) 2008 by the American Society of Regional Anesthesia and Pain Medicine.
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doi:10.1016/j.rapm.2007.07.010
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