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PAIN MEDICINE

Preincisional Intravenous Pentoxifylline Attenuating Perioperative Cytokine Response, Reducing Morphine Consumption, and Improving Recovery of Bowel Function in Patients Undergoing Colorectal Cancer Surgery

Chueng-He Lu, MD^*, Pei-Chieh Chao, MD, Cecil O. Borel, MD, Chih-Ping Yang, MD^*, Chun-Chang Yeh, MD^*, Chih-Shung Wong, MD PhD^*, and Ching-Tang Wu, MD^*

Departments of *Anesthesiology and Colon and Rectal Surgery, Tri-Service General Hospital and National Defense Medical Center, National Defense University, Taipei, Taiwan; 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 and 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

	Abstract

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Cytokine release during surgery can produce a long-lasting hyperalgesia. Thus, preoperatively-administered cytokine inhibitors might reduce the production of cytokines, decreasing central nervous system sensitization and improving the quality of postoperative pain relief. We investigated the hypothesis that preincisional IV pentoxifylline (PTX) treatment could attenuate the release of proinflammatory (tumor necrosis factor, interleukin (IL)-1ß, IL-6, and IL-8) and antiinflammatory (IL-1 receptor antagonist) cytokines in patients who underwent elective colorectal cancer surgery. Forty patients were randomly assigned to 1 of 2 groups of 20 each: the PTX group received a PTX 5 mg/kg IV infusion before the induction of anesthesia, whereas the control group received an equal volume of normal saline. Venous blood samples were obtained at frequent intervals. After surgery, all patients received patient-controlled analgesia (PCA) morphine for postoperative pain relief. Patients in the PTX group exhibited longer PCA trigger times, less morphine consumption, and a faster return of bowel function compared with patients in the control group. Moreover, the plasma levels of IL-6, IL-8, and IL-1 receptor antagonist were less in the treatment group, and there was no significant difference in wound infections, tumor recurrence, or metastatic rates between groups during a 2-yr follow-up.

IMPLICATIONS: Preoperative IV pentoxifylline improved postoperative pain, resulting in diminished morphine consumption, faster return of bowel function, and attenuated production of interleukin (IL)-6, IL-8, and IL-1 receptor antagonist in the perioperative period, but it did not increase the risk of complications in this small patient group.

	Introduction

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Tissue injury associated with surgery sets off an inflammatory reaction accompanied by increased levels of proinflammatory cytokines. These proinflammatory cytokines can induce peripheral and central nervous system (CNS) sensitization, leading to hyperalgesia (1). Because of the feedback cascade between nociception and proinflammatory cytokines, it is also possible that the experience of pain contributes to increased proinflammatory cytokines. At the same time, antiinflammatory cytokine levels also increase, tending to maintain homeostasis (2).

The immunosuppressive effects of painful experiences have been studied in both humans and animals for many years. Because pain mechanisms have been shown to mediate the immunosuppressive effects of surgery (3), adequate pain management is a vital adjunct to the overall care of surgical patients. One of the goals of preemptive pain management might be modulation of the inflammatory response, but the main goal is the reduction of pain and analgesic requirements. However, we try to modulate the immune response by reduction, but not ablation, of proinflammatory and antiinflammatory cytokine release, because ablation of the immune reaction to surgery could increase the rate of infection and tumor recurrence.

Presently available proinflammatory cytokine antagonists are large proteins, antisera, or soluble receptor/antibody hybrids. None of these effectively crosses the blood-brain barrier. Pentoxifylline (PTX) is a methylxanthine that inhibits phosphodiesterase IV with rheologic and immunomodulatory effects. Its main clinical use is in the treatment of intermittent claudication, acute ischemic stroke, vascular dementia, and Alzheimer-type dementia, for which increases in erythrocyte membrane fluidity and reduced plasma viscosity are believed to improve capillary blood flow (4). PTX can inhibit the production of tumor necrosis factor (TNF), interleukin (IL)-1, oxygen free radical generation from glial cells, and IL-6 production. It can also increase extracellular adenosine by inhibition of glial adenosine transporters and can cross the blood-brain barrier (4). Therefore, PTX has potential for clinical pain management (4). Preinjury intrathecal or intraperitoneal PTX injection increased the nociceptive threshold for mechanical stimuli and inhibited pain-related behavior in the formalin test in rats. Preoperative IV PTX also provided preemptive analgesia in patients who underwent cholecystectomy, by attenuating the production of IL-6 and TNF (5).

IL-6 is the main proinflammatory cytokine. It correlates with the severity of surgery and the magnitude of the tissue injury (6) and can lead to hyperalgesia (1). IL-1ß, TNF, and IL-8 can also induce central sensitization (7). These proinflammatory cytokines could modulate pain indirectly by altering pain transmission via cytokine-induced release of other neuroactive substances—such as nitric oxide and other oxygen free radicals, prostaglandins, and excitatory amino acids—from microglial and astrocytes. These substances could be the proximate cause for the pain-enhancing effects of proinflammatory cytokines (4). In addition, IL-1 receptor antagonist (RA) was released at sites of inflammation, and this limits inflammatory hyperalgesia (8).

Colorectal surgery is associated with higher levels of IL-6 than any other operation (6) and is often associated with postoperative ileus. The large doses of opioids used to relieve postoperative pain might also increase the likelihood of postoperative ileus. Recently, the upregulation and release of proinflammatory cytokines after surgery has been shown to play an important role in postoperative ileus (9). Therefore, we investigated the effect of preoperative IV PTX treatment on the responses of proinflammatory (TNF, IL-1ß, IL-6, and IL-8) and antiinflammatory (IL-1RA) cytokines and on the management of pain and recovery of bowel function during the perioperative period.

	Methods

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This study was approved by our IRB. Written, informed consent was obtained from all patients. Forty ASA physical status I or II patients, aged 40–80 yr, scheduled for elective colorectal cancer surgery were included and randomly allocated by selection of sealed envelopes to one of two groups: PTX or control. On the basis of retrospective data from our institution in the same surgical population, a power analysis was performed that used morphine consumption as the primary variable. We calculated a sample size so that a between-group mean difference in morphine consumption of 10 mg would permit a one-tailed Type I error rate of = 0.05 with a power of 80%. This analysis indicated that a sample size of at least 14 patients per group was necessary. Patients who had received opioids or nonsteroidal antiinflammatory drugs within the week preceding the study, who had distant metastasis, and who were likely to receive blood transfusion during the perioperative period were not included in this study. All procedures were performed by the same surgeon. On the preoperative visit by the anesthesiologist, patients were familiarized with the visual analog pain scale (VAS), with end-points labeled "no pain" and "worst possible pain," and were instructed on the use of the patient-controlled analgesia (PCA) pump (Pain Management Provider; Abbott, Chicago, IL). The PTX group patients received IV PTX 5 mg/kg (n = 20), and the control group patients received the same volume of normal saline drip for 10 min (n = 20) 30 min before surgery. The study drugs (PTX and normal saline) were prepared by the hospital pharmacy in identical containers marked with the name of the project, the investigator’s name, and consecutive numbers. Patients and investigators were blinded to the PTX or control premedication (double-blind).

For all patients, 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 blood pressure. Respiratory frequency and tidal volume were adjusted to maintain the end-tidal carbon dioxide level at 35–45 mm Hg. Esophageal temperature was maintained at 35°C–37°C. For fluid therapy, all patients received a balanced salt solution at 6 mL·kg^–1·h^–1 perioperatively and 2 mL·kg^–1·h^–1 after surgery. No additional opioids were given during the operation. Standard monitors included pulse oximetry, electrocardiography, and noninvasive arterial blood pressure. 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 PCA pump and received PCA morphine (morphine 1.0 mg/mL, 1.0 mg per time; lockout time was 5 min without a 4-h limitation or continuous background infusion), titrated by the acute pain service team and until the resting VAS was 3. A VAS was used to assess pain intensity at rest and after coughing at 1, 2, 4, 24, 48, and 72 h after the completion of surgery.

We recorded the time to the first PCA trigger, total morphine consumption, the time to the first passage of flatus, perioperative blood loss, and adverse effects related to morphine (drowsiness, dizziness, nausea, and vomiting) for 72 h after the operation. The perioperative blood loss was measured in the surgical suction container and by weighing sponges and laparotomy pads before and after use. We defined the return of bowel function as the first passage of flatus. All postoperative observations were made by a study nurse. Adverse effects were treated as necessary.

Blood samples were obtained 10 min before the PTX infusion, 1 and 2 h after skin incision, at the end of surgery, and after surgery at 6, 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 commercially available 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 period of time. Each well was then aspirated, and the plates were washed with the provided buffered surfactant. 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. All values are reported as picograms per milliliter. The intraassay and interassay coefficients of variation of the immunoassay kits ranged from 5% to 10%. Cross-reactivity with other factors was negligible in all cytokine assays.

Parametric values were analyzed with Student’s t-test. Data were analyzed for each measure by using analysis of variance with repeated measures, and Bonferroni’s procedure was conducted as appropriate, correcting for multiple comparisons. Adverse effects were analyzed with the ² test. Probability values of P < 0.05 were considered significant. The results are expressed as mean ± SD.

	Results

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The groups were similar in age, body weight, height, male/female ratio, duration of surgery, and average end-tidal concentration of desflurane (Table 1). Patients in the PTX group exhibited a longer time to trigger PCA (43.3 ± 16.3 min versus 16.5 ± 4.6 min; P < 0.0001), less morphine consumption (18.6 ± 2.5 mg versus 31.6 ± 4.4 mg; P < 0.0001), and a faster return of bowel function (70.9 ± 5.3 h versus 78.6 ± 6.5 h; P = 0.0002), without an increased incidence of adverse side effects over a 3-day observation period after surgery (Fig. 1, Table 2). Pain scores revealed similar trends between measurements taken at rest and during coughing. There were small but significant differences between the study groups (P < 0.005) for VAS during coughing. However, there was no significant difference (P = 0.66) for VAS during rest (Fig. 2). These data indicate that patients self-administered a smaller amount of morphine to achieve a similar level of analgesia; this was the most important demonstrated benefit. Eight patients in the control group and four patients in the PTX group experienced morphine-related adverse effects such as nausea and/or vomiting: six versus three were treated with prochlorperazine 5 mg IV, and two versus one were treated for pruritus with diphenhydramine 30 mg IV, respectively. However, there was no significant difference between groups (Table 2).

View larger version (14K): [in this window] [in a new window]   Figure 1. The patient-controlled analgesia morphine consumption during the 3-day observation after surgery for patients of the two groups: pentoxifylline (PTX) or control. Morphine consumption was significantly less in patients of the PTX group throughout the observation period. Values are mean ± SD. D1, D2, and D3 = postoperative Day 1, Day 2, and Day 3. *P < 0.05 compared with PTX group (GP) patients.

View larger version (54K): [in this window] [in a new window]   Figure 2. Visual analog scale pain scores at rest (A) and during coughing (B) for 1 h to 3 days after surgery for patients in the two groups: pentoxifylline (PTX) or control. Resting pain intensity was not significantly different between groups; however, coughing pain intensity was significantly greater in patients in the control group compared with PTX group patients. Values are mean ± SD. D1, D2, and D3 = postoperative Day 1, Day 2, and Day 3; GP = group. * P < 0.05.

View larger version (24K): [in this window] [in a new window]   Figure 3. The mean plasma levels of interleukin (IL)-6 (A), IL-8 (B), IL-1 receptor antagonist (RA) (C), tumor- necrosis factor (TNF) (D), and IL-1ß (E) concentrations (mean ± SD). The control group had significantly higher levels than the PTX group at the end of the surgical procedure and at 6, 12, and 24 h after surgery. IL-1RA was significantly increased even at 2 h after skin incision compared with the PTX group. PTX = pentoxifylline; GP = group; 0 = baseline; 1and 2 = 1 and 2 h after skin incision; END = end of the surgical procedure; 6, 12, and 24 = 6, 12, and 24 h after operation. #P < 0.0001, postoperative versus baseline levels in both groups; *P < 0.0001, PTX versus control group; $P < 0.0001, postoperative versus baseline levels in control group.

	Discussion

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The major findings of our study are that preoperatively administered IV PTX (5 mg/kg) produces a morphine-sparing effect, prolongs the time to first PCA morphine use, and speeds recovery of bowel function without increasing the incidence of adverse side effects after colorectal surgery. In addition, IV PTX produced fewer proinflammatory and antiinflammatory cytokines and thus attenuated surgery-induced immune alterations. These results are consistent with those of Wordliczek et al. (5), who showed that IV PTX 10 mg/kg provided beneficial postoperative analgesic effects and inhibited TNF and IL-6 production in patients undergoing cholecystectomy.

IL-6, the main proinflammatory cytokine, is produced in substantial quantities at the surgical wound (10) and then enters the systemic circulation, where its concentration correlates with the severity of surgery and the magnitude of the tissue injury (6). IL-6 is produced as early as two to four hours after tissue damage (11). In this study, IL-6 was increased at the end of surgery (approximately three hours), reached a peak at six hours after surgery, and then declined progressively in both groups. Moreover, IL-6 can induce peripheral and CNS sensitization, leading to hyperalgesia (1). In this study, the altered IL-6 values between groups may have been a direct effect of PTX, because both groups had similar degrees of tissue injury and had the same anesthetic and surgical management. Therefore, we suggest that the effect of PTX might be due to attenuation of IL-6 production. Our results are consistent with other studies showing attenuated IL-6 production in sepsis and surgery after PTX administration (5,12). We did not continue to measure the level at 48 and 72 hours after surgery because the levels of IL-6 in the plasma reached preoperative values at 24 to 36 hours after surgery in our study (11).

In this study, we did not detect changes in IL-1ß; it is not readily released into the systemic circulation, and its plasma levels may be very low even if inflammation is severe (5,13). Like IL-1ß, TNF exhibited a no change over time and was not different between groups in this study. However, several studies have reported significant postoperative TNF levels measured in wound and peritoneal fluids, although perioperative circulatory TNF changes were undetectable (14). Therefore, it is still conceivable that levels of TNF in the area of tissue injury were higher than those in the plasma (14). We believe that IL-1ß and TNF still play important roles in mechanical nociceptor hypersensitivity resulting from the concomitant endogenous release of eicosanoids and sympathomimetic mediators (15). In contrast, Wordliczek et al. (5) found that IV PTX 10 mg/kg provided a significant inhibition of TNF in patients who underwent cholecystectomy, although the surgical trauma was less than ours. This might be due to different surgical and anesthetic techniques and larger doses of PTX in their study.

IL-8 is released by activated macrophages and endothelial cells and may be a humoral link between tissue injury and sympathetic hyperalgesia (16). Sachs et al. (15) found that IL-8 induced persistent mechanical nociceptor hypersensitivity via sympathetic amines. Moreover, small doses of PTX were shown to significantly enhance chemotaxis and phagocytosis of neutrophils in an in vitro study (17); thus, PTX may increase IL-8 production. IL-8 production can be rapidly induced by IL-1 and TNF (18). Therefore, in this study, preincisional IV PTX suppressed IL-8 production by attenuating the production of IL-1 and TNF.

We demonstrated a significant difference in the levels of IL-1RA between groups over time. IL-1RA is a naturally competitive inhibitor of IL-1ß and competes with IL-1ß for binding on the cell-surface receptors of effector cells. Therefore, IL-1RA has often been assumed to provide a marker for the presence of IL-1ß (13). Fischer et al. (19) showed that IL-1RA was expressed with IL-1ß, signaling the acute phase response and correlating well with the grade of inflammation. In addition, Cunha et al. (8) demonstrated that IL-1RA was released at sites of inflammation and limited inflammatory-induced hyperalgesia. IL-1RA acts as a functional antagonist by inhibiting the production of inflammatory cytokines, reducing the inflammatory response (20), and antagonizing substance P release, thus providing the analgesic effect (4). Similarly, patients who have chronic pain with fibromyalgia (21) and rotator cuff disease (22) have higher levels of IL-1RA. Therefore, we speculate that to have achieved immune homeostasis, the control group patients experienced more intense postoperative pain and thus released higher levels of IL-1RA, which antagonized substance P release and provided an analgesic effect.

Glial activation and its associated proinflammatory cytokine release appear to drive exaggerated pain states within the CNS. PTX can suppress microglial and astrocyte activation, inhibit microglial proliferation, increase antiinflammatory cytokine production, enhance uptake of extracellular excitatory amino acids by glial activation, and increase extracellular adenosine by inhibition of glial adenosine transporters (4). Furthermore, the increased adenosine can activate potassium and chloride conductances in neurons that limit synaptically-evoked depolarization, thus counteracting calcium ion influx through voltage-dependent and N-methyl-D-aspartate receptor-operated ion channels and diminishing CNS sensitization (23). Thus, we postulated that PTX attenuates the production of cytokines and provides good postoperative pain relief by two mechanisms: a central effect by inhibiting the production of cytokines from glial cells and a peripheral effect by increasing extracellular adenosine and then attenuating CNS sensitization.

Colonic surgery is associated with severe postoperative pain. In addition, the use of traditional drugs such as opioids for postoperative pain relief contributes to ileus (24). Therefore, both pain and opioid use can diminish bowel function and postoperative cause ileus. Hence, to some degree, improved analgesia and reduced PCA opioid administration contribute to minimizing postoperative ileus. Recently, upregulation and release of proinflammatory cytokines after surgery was demonstrated to contribute to postoperative ileus (9). Therefore, the finding that PTX group patients exhibited faster recovery of bowel function might have been due to the multiple effects of PTX by attenuating cytokine production and diminishing morphine consumption. Although bowel function was restored significantly earlier in the PTX group, discharge from the hospital was similar for both groups. This is because patients who were ready for discharge were kept in the hospital by surgical convention for removal of sutures and patient expectation for length of stay.

With clinical administration of immunosuppressant drugs, iatrogenic complications such as sepsis and wound infection must be considered. A study by Josaki et al. (17) found biphasic dose-dependent actions of PTX in an in vitro experiment. Large concentrations of PTX inhibited superoxide production and phagocytosis. Small concentrations of PTX, however, were shown to significantly enhance chemotaxis and phagocytosis of neutrophils in vitro. Similarly, large doses of PTX have also been reported to completely eliminate IL-1 production, which may decrease the host’s ability to mount an antimicrobial attack (25). Nelson et al. (26) showed that PTX 5 mg/kg reduced the production of cytokines in a rat model of acute peritonitis, and this reduced production was associated with an improved survival rate. Thus, it appears that modulation of the inflammatory response by reduction, and not ablation, of proinflammatory and antiinflammatory cytokine release may be an approach to maintaining cell and organ function by using small doses of PTX. Consistent with the present study, PTX 5 mg/kg attenuated proinflammatory and antiinflammatory cytokines. Although it did not increase wound infection and tumor recurrence or metastatic rates, the sample size was too small to make conclusions, and this was not the primary hypothesis. The study of Wordliczek et al. (5) did not measure antiinflammatory cytokines or report wound-infection rates. In addition, the dosage of PTX they used might be too large for clinical practice.

In conclusion, preincisional IV PTX 5 mg/kg improved postoperative pain management, resulted in prolonged time to first PCA morphine trigger, diminished opioid consumption, and increased recovery of bowel function. This might have been due to both central and peripheral effects by attenuating the production of IL-6, IL-8, and IL-1RA in the perioperative period. Meanwhile, this immunomodulation by PTX did not increase blood loss, wound infection, or tumor recurrence or metastatic rates in this small patient group.

	Acknowledgments

 
Supported by Grant NSC 90-2314-B-016-061 from the National Science Council of Taiwan, Republic of China.

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999