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Plasma Levels of Interleukin-6 and Interleukin-10 Are Affected by Ketorolac as an Adjunct to Patient-Controlled Morphine After Abdominal Hysterectomy

Kim, Myung Hee M.D., Ph.D.; Hahm, Tae Soo M.D., Ph.D.

The Clinical Journal of Pain: March 2001 - Volume 17 - Issue 1 - p 72-77
Special Topic Series: Musculoskeletal Pain

Objective: Because morphine affects various immune functions, patient-controlled analgesia with morphine may further deteriorate the immune mechanisms after surgery. Therefore, the purpose of this study was to determine differences between morphine patient-controlled analgesia and a combination of morphine and ketorolac in interleukin-6 and interleukin-10 responses, and in analgesia and morphine-related side effects.

Design: Prospective study.

Patients: Twenty-two patients who underwent abdominal hysterectomy were classified randomly into two groups: (1) patient-controlled analgesia with morphine; and (2) patient-controlled analgesia with a combination of morphine and ketorolac. Blood samples to measure cytokines were collected at preoperatively, immediately postoperatively, and 2 hours, 4 hours, and 24 hours postoperatively.

Outcome Measures: Plasma was separated and frozen until the analysis of cytokines using enzyme-linked immunosorbent assays. Postoperative pain was assessed using a visual analog score. Sedation was checked based on a protocol developed at the Samsung Medical Center.

Results: In the two groups, interleukin-6 increased immediately postoperatively, and it remained consistent for 24 hours. Interleukin-10 concentrations peaked at 2 hours postoperatively and progressively decreased. Cytokine concentrations between the two groups were significantly different for interleukin-6 24 hours postoperatively (p = 0.026) and for interleukin-10 4 hours postoperatively (p = 0.045). Total analgesic use was not different, but morphine consumption was significantly different (p = 0.037 at 4 hours postoperatively, p = 0.015 at 24 hours postoperatively). Pain scores, sedation, and side effects were unaffected by the patient-controlled analgesia regimen.

Conclusions: The authors conclude that supplementation using ketorolac plus administration of morphine modifies cytokine responses and may contribute to immune augmentations during postoperative periods.

Department of Anesthesiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

Received March 13, 2000; revised September 5, 2000; accepted September 20, 2000.

Address correspondence and reprint requests to Dr. Myung H. Kim, Department of Anaesthesiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Kangnam-Ku, Seoul, South Korea 135-710; e-mail:

Combining nonsteroidal anti-inflammatory drugs (NSAIDs) with opiates rather than using opiates alone has become increasingly popular because of sufficient analgesia and lack of opioid-induced side effects.1 In addition to pain management, maintenance of immune homeostasis is important for a patient in regard to qualitative care and early postoperative discharge. Numerous studies have been undertaken to reduce postoperative stress response, therefore improving postoperative prognosis.2-5 Patients who were treated preoperatively using an NSAID (indomethacin) showed an improved postoperative prognosis.5 Moreover, Hun et al.6 reported that ketorolac eased the effects of cytokines in an ex vivo study, which indicates the involvement of prostanoids.

Surgical stress or major trauma influences a shift in the balance of type 1/type 2 T helper (Th1/Th2) cells toward Th2.7,8 Th2 cells secrete cytokines interleukin-4 (IL-4), interleukin-5, interleukin-6 (IL-6), interleukin-10 (IL-10), and interleukin-13 and stimulate antibody production. Clinical implication of surgery-induced up-regulation of Th2 response for the patients increases susceptibility to infection and allergic type autoimmune diseases.8,9 Interleukin-6 is categorized as a proinflammatory cytokine and IL-10 is classified as an anti-inflammatory cytokine, depending on physiologic function. To maintain immune homeostasis, a balance between these two cytokine effects is necessary. The imbalance between proinflammatory and anti-inflammatory cytokine was associated with reduced survival.10

Therefore, the purpose of this study was to investigate whether the addition of an equianalgesic dose of ketorolac to morphine patient-controlled analgesia in patients after abdominal hysterectomy can alter the concentrations of the proinflammatory cytokine IL-6 and the anti-inflammatory cytokine IL-10, and analgesic scores and potential side effects.

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Twenty-two women (American Society of Anesthesiologists physical status I or II) ranging from 37 to 51 years of age who underwent abdominal hysterectomy were enrolled in this study. The study was approved by the ethics committee of the Samsung Medical Center, Sungkyunkwan University School of Medicine, and informed consent was obtained. Patients with underlying diseases, such as renal or peptic ulcer disease and bleeding disorders, or to whom anticoagulant medications were being administered and who had known sensitivity to morphine or NSAIDs were excluded from this study. No premedication was administered before operative procedures. After arrival in the anesthetic room, blood pressure, heart rate, and peripheral oxygen saturation were monitored using noninvasive techniques. Induction of anesthesia was performed using 5 mg/kg thiopental and 0.1 mg/kg pancuronium, followed by laryngoscopy and intubation. Anesthesia was maintained using 2.0-3.5 vol% enflurane and 50% nitrous oxide in oxygen. End-tidal pressure of carbon dioxide was maintained between 30-35 mm Hg by adjusting the respiratory frequency and tidal volume. Esophageal temperature was maintained at 35-37°C. All patients received Hartmann solution during surgery, and blood loss during surgery was determined by examining swabs and suction aspirates. At the end of the operation, neuromuscular block was antagonized using pyridostigmine and glycopyrrolate. In the postanesthesia care unit, each patient was assigned to one of two groups: the morphine group (M group) or the morphine and ketorolac group (MK group). The analgesic mixture was administered using the PCA device. As Picard et al.11 suggested, we used the mixture of morphine and ketorolac in the same PCA device without the occurrence of chemical instability. Because it is known that ketorolac is an equianalgesic to approximately a third of a dose of morphine, the PCA device contained 1 mg/mL morphine for the M group, and 1.5 mg/mL ketorolac plus 0.5 mg/mL morphine for the MK group after a loading dose of 0.1 mg/kg morphine. The PCA system was programmed to deliver an initial dose of 1 mL/demand with a 10-minute lock-out interval and no continuous back-ground infusion. The patient was asked to attempt self-administration whenever she was in pain. The actual amount of administered analgesics was recorded by an investigator at 2, 4, and 24 hours postoperatively. Patients were observed closely for side effects during PCA. All possible side effects of PCA were treated using the following protocol: when a respiratory rate is less than 10 breaths/minute, accompanied by deep sedation, 0.2 mg naloxone (intravenous) is provided as needed. When pruritus is detected, pheniramine maleate (25 mg) is injected, and, if the case is severe, another dose of naloxone (0.1 mg) is administered. Occurrence of nausea and vomiting was documented and treated using droperidol (0.8 mg) intravenous injection or using macperan (10 mg), as necessary. When a systolic pressure below 90 mm Hg is detected and accompanied by dizziness, Hartmann solution (500 mL) and ephedrine (5 mg) is administered. Analgesic score was graded on a scale from 0 (no pain) to 100 mm (maximum pain) using the visual analog scale score (VAS). Degree of sedation was graded on a five-point scale: 0 (awake), 1 (awake/drowsy), 2 (asleep/easily responsive to verbal commands), 3 (asleep/responsive to tactile stimulus), and 4 (no response to any stimulus). Postoperative incidence of urinary retention and the time of first bowel movement also were recorded.

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Measurement of venous cytokines concentration

Venous blood samples were collected five times throughout the study period (10 minutes before induction, immediately after surgery, and 2 hours, 4 hours, and 24 hours postoperatively. Blood samples immediately were refrigerated at 4°C and subsequently centrifuged (400 rpm for 10 minutes) within 30 minutes. Plasma samples were centrifuged rapidly and refrigerated immediately at −70°C until all samples were collected. The analyses of IL-6 and IL-10 were performed via enzyme-linked immunosorbent assay (ELISA) using commercial reagents (Quantikine Human Cytokine Assays; R&D Systems, Minneapolis, MN). The detection limit of this assay was 1.98 pg/mL for IL-6 and 4.2 pg/mL for IL-10. Assessment of analgesic effectiveness and degree of sedation were made in the same time period as that of the blood sampling for cytokine analysis.

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This study was conducted using the double-blind method. Demographic and clinical data of the two groups were compared using the Student t test. Because IL-6 and IL-10 concentrations and morphine consumption were not distributed normally, the Mann-Whitney test was used to compare the two groups at the same time period. Within the same group, comparison of IL-6 or IL-10 concentration in response to baseline value was performed using the Friedman repeated measures ANOVA on ranks and the Dunnett method. Interleukin-6 or IL-10 data are presented as the median. Less than 0.05 for p value was considered to be significant. Because of the small number of patients in our study, risk of type II error may be expected. Therefore, the negative findings should be interpreted cautiously.

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No significant differences in age, weight, height, and clinical data, such as duration of anesthesia, blood loss, and amount of total fluid administered between the two groups, were found (Table 1). Mean cumulative analgesic consumption was not different between the two groups, but morphine consumption was different between the two groups at 4 hours (p = 0.037) and at 24 hours (p = 0.015) postoperatively (Table 2). The degree of analgesia and sedation and the incidence of side effects, such as nausea, dizziness and urinary retention, were not different between the groups.





The plasma concentrations of IL-6 and IL-10 during the study period are shown in Figure 1. Interleukin-6 concentrations of the two groups increased significantly during the immediate postoperative period and stayed significantly higher than those before the induction of anesthesia during the study. The IL-6 value was significantly different between the groups 24 hours postoperatively (38.4 [range = 22.9-156.2] pg/mL for the M group vs. 24.5 (range = 9.5-106.6) pg/mL for the MK group, p = 0.026). Similar to the IL-6 values, IL-10 concentrations within the groups increased significantly during the immediate postoperative period, peaked 2 hours postoperatively, and subsequently decreased. A comparison of IL-10 values between the two groups showed a small but statistically significant change occurred 4 hours postoperatively (5.7 (range = 4.8-7.4) pg/mL for the M group vs. 9.3 (range = 4.8-19.2) pg/mL for the MK group; p = 0.045).

FIG. 1

FIG. 1

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Analgesic effects and side effects

Although a balanced combination of morphine and ketorolac can provide more efficient analgesia and reduce morphine requirements and opioid-related side effects, such as respiratory depression, pruritus, nausea and vomiting during the postoperative period,1,11 the current study showed no significant differences in analgesic doses and in pain scores between the groups. Our results and the results of other studies, show that analgesia may be influenced by other factors, such as environmental and psychologic factors.

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Responses of interleukin-6 and interleukin-10

Undergoing major surgery causes alterations in cytokines release that may be related to postoperative morbidity.12 Significant postoperative changes were shown in plasma concentrations of Th2 cytokines IL-6 and IL-10 after abdominal hysterectomy in the current study. The IL-6 values increased significantly immediately after surgery and remained consistent for the duration of the study period for the two groups. The peak response of IL-6 at 4 hours after the start of surgery in our study confirmed the observation of values found in previous pelvic surgery.13 As an important mediator of the host defense mechanisms and the systemic inflammation responses, IL-6 is produced early after tissue damage, with the magnitude of release being determined by the severity of the surgical trauma.14 In the comparison of IL-6 concentrations between the two groups, there was less of a IL-6 response in the MK group 24 hours postoperatively than the M group. Notably, the mean dose of 35 mg ketorolac in the MK group (24 hours postoperatively) was relatively small, but significant differences occurred in IL-6 response.

Several attempts have been made in anesthesiology to augment the immune response and to modify the responses of surgical trauma, such as lymphopenia and endocrine changes. The choice of anesthetic agent may influence the perioperative cytokine response by changing the neuroendocrine stress hormones. Documentation shows that, compared with general anesthesia, epidural anesthesia and spinal anesthesia alleviate surgery-induced immunosuppression.15,16 Blocking of the peripheral nervous system using regional anesthesia was suggested for the mechanism of attenuation of the surgical stress responses. In a study by Pirttikangas et al. that compared total propofol infusion with isoflurane anesthesia, total propofol infusion was theoretically beneficial because it increased the percentage of Th cells in response to opthalmic surgery in elderly persons and to hysterectomy in middle-aged patients.17,18 There are insufficient data to explain the effect of an inhalation anesthetic on neuroendocrine, metabolic, and immune changes in response to surgical procedures in human studies.

To alleviate cytokine response from excessive surgical stress, we evaluated the effects of postsurgical administration of ketorolac for hysterectomy. Prostaglandin has long been considered a trigger factor of immunosuppression after surgery. Prostaglandin exerts most of its physiologic functions through the activation of adenyl cyclase and the production of intracellular cyclic adenosine monophosphate (cAMP).19 It has been suggested that one of the mechanisms for IL-6 release is increase in cAMP release.20 Therefore, the cyclooxygenase inhibitor ketorolac may have an important role in the attenuation of IL-6 response via inhibition of prostaglandin E2 (PGE2) and cAMP. One can therefore consider the possibility that administration of an NSAID may block the IL-6 responses by PGE2. Opioid-induced attenuation of IL-6 release after surgery is also explained by opioid binding to immunocyte receptors and results in the inhibition of adenyl cyclase activity followed by the reduction of cAMP.21 Crozier et. al13 reported that, compared with isoflurane, opioid analgesics have an important role in reducing the magnitude of IL-6 response in abdominal surgery. Although it is true that a decreased amount of morphine was used in the MK group in the current study, such a difference does not explain the results in IL-6 response.22

In the current study, the altered IL-6 values between the groups may be a direct effect of ketorolac because the same type of surgery, which would produce similar degrees of tissue damage, and anesthetic regimens were used. Duration of surgery and blood loss during operative procedures, which might also alter cytokine responses, also were similar in the two groups. Therefore, we suggest that the reduced production of IL-6 24 hours postoperatively with the addition of ketorolac to the morphine PCA be mediated by the inhibition of prostaglandin and cAMP.

The anti-inflammatory cytokine IL-10 has an important role in attenuation of the overproduction of proinflammatory cytokines.23,24 Anti-inflammatory cytokines also are increased during surgery in the circulating blood to maintain a balance with proinflammatory cytokines in this complex network.25 We observed that the maximum value of IL-10 also was achieved 2 hours postoperatively in the two groups, which correlates with the increase of IL-6 levels. In a study of relations between IL-10 expression and morphine dosages in patients undergoing cardiac surgery, there were no differences in IL-10 release between high- and low-dosage opioids.22 We found a small but statistically significant increase of IL-10 concentration 4 hours postoperatively in the MK group. Anti-inflammatory effects of IL-10 and PGE2 synthesis seem to affect each other. Prostaglandin E2 played a key role in the induction of IL-10 in human monocytes, and IL-10 in turn inhibited PGE2 production.26 Niiro et al.27 suggested that recombinant IL-10 inhibited PGE2 production in endotoxin-stimulated monocytes in a dose-dependent manner. Shimizu et al.28 also showed that NSAID increased the IL-10 response in murine peritoneal macrophages infected with mycobacterium avium complex in vitro. This alteration of IL-10 concentration by NSAID seems to induce anti-inflammatory effects by inhibiting PGE2 production through the IL-10 response.

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In conclusion, using PCA with a combination of morphine and ketorolac decreased IL-6 concentrations 24 hours postoperatively and increased IL-10 concentrations 4 hours postoperatively versus using only morphine PCA. The changes in IL-6 and IL-10 that we observed, although statistically significant, are small and may not affect the outcome of the patients classified as American Society of Anesthesiologists physical status I or II. However, the immunomodulatory effect of ketorolac on IL-6 and IL-10 production may have significant clinical implications.

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Abdominal hysterectomy; Cytokines; Interleukin-6; Interleukin-10; Ketorolac; Morphine; Patient-controlled analgesia; Surgery

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