Introduction

Surgical trauma leads to changes in the metabolic, endocrine, and immune systems. Tissue damage, surgical stress, and pain cause afferent neuronal stimulation and the activation of cellular and humoral immune pathways that are associated with local inflammatory reactions and the accompanying elevations in the biological mediators such as cytokines (1,2). Proinflammatory cytokines, especially IL-6 and TNF-α, play an important role in the development of hyperalgesia and mechanical allodynia (3). The management of analgesia may affect neuroendocrine responses and attenuate proinflammatory cytokine production. Preemptive analgesia is a method in which treatment begins before the surgical stimulus and reduces the central and peripheral sensitization (4).

Our objective was to evaluate whether a preemptive analgesia method that used a continuous epidural infusion could attenuate cytokine production postoperatively in pediatric patients undergoing urological surgery. We chose an antiinflamatory cytokine - IL-2 and a proinflamatory cytokine - TNF-α as a marker of the efficacy of preemptive analgesia on neuroendocrine response induced by pain.

Methods

Patients

After obtaining ethical approval of the University Hospital (no:18447) and written consent of parents, 60 children aged 3-12 years (American Society of Anesthesiologists [ASA] physical status I-III) were included the study. Exclusion criteria were a recurrent operation, congenital cardiac defects, malignancy, and an endocrine or immune disease. All patients were scheduled for elective ureteropelvic junction obstruction or vesicoureteral reflux surgery. The participants were randomly assigned to receive one of the two methods of analgesia and postoperative pain. Thirty-one patients received general anesthesia and a continuous epidural infusion (preemptive epidural analgesia [Preempt EA] group), whereas twenty-nine patients received general anesthesia and a perioperative ultra short-acting intravenous opioid infusion (postoperative epidural analgesia [Postop EA] group). Postoperative analgesia control was provided by continuous epidural infusion in both groups.

Anesthesia and Analgesia

Electrocardiogram, arterial blood pressure (noninvasively prior to the induction of anesthesia, invasively thereafter), oxygen saturation, ETCO2, and temperature were monitored in all patients during the surgery. Anesthesia was induced with intravenous 1 μg/kg fentanyl, 3-5 mg kg-1 thiopental, and 0.5 mg kg-1 atracurium. The patients were intubated and ventilated with 40% oxygen at 12-18 breaths per minute, and the tidal volume was adjusted to maintain an end tidal CO2 of 30-35 mmHg and a peak airway pressure of 15-20 cm H2O. Anesthesia maintained with 2-3%sevoflurane in air-oxygen mixture. After the anesthesia induction, the patients were turned onto left lateral position for insertion of epidural catheter. The epidural catheter was placed at the T12-L1 or L1-L2 interspace and advanced 4-5 cm. A test dose of 2 ml of 1% lidocaine was used to ensure a spinal placement did not occur.

Thirty minutes before the surgical incision, a continuous infusion of 0.1% bupivacaine plus 0.02 mg ml-1 morphine at a rate of 0.4 ml kg-1 h-1 (maximal dose=6 ml) was initiated in the Preempt EA group. The epidural infusion was continued without cessation through the postoperative period. The analgesia provided to the Postop EA group was an infusion of remifentanyl at a rate of 0.1-0.25 μg kg-1 min-1 that was initiated after the induction of anesthesia. After the peritoneal closure, an infusion of 0.1% bupivacaine plus 0.02 mg ml-1 morphine at a rate of 0.4 ml kg-1 h-1 was administered epidurally for postoperative analgesia. The time of the analgesic request during three time periods, in the recovery room (t1), the first 6 h postoperatively (t2), and between 6 to 24 h after surgery (t3), was recorded. A continuous infusion of Ringer’s lactate solution was given (the 4:2:1 rule was followed), and 6% hydoxyethyl starch was added when the mean arterial pressure dropped 30% below the baseline level. The mean arterial blood pressure and heart rate were maintained within 20% of their baseline values.

Four milliliters of blood were collected for plasma TNF-α and IL-2 analysis before the induction of anesthesia (T1), 1 h after surgical peritoneal closure (T2), and 24 h after surgery (T3). The patients were extubated following reversal of the neuromuscular block. All patients were transferred to a patient room after 2 h in the recovery unit. Crystalloid and colloid solutions were infused during the postoperative period. FACES pain scale scores were assessed by an anesthetist based on drawings of five faces that corresponded to five levels of pain (scores ranged from 0-6 with 0 = no pain and 5 = worst pain) and were recorded 1 h and 24 h after surgery. Intravenous paracetamol (15 mg kg-1) was infused to all patients with a FACES pain score of at least 3 during the postoperative period. Sedation scores were evaluated at the same time as pain scores with the University of Michigan Sedation Scale (0 = awake and alert and 4 = unarousable to stimuli). The pain and sedation scoring were done by another anesthetist group who were blinded to the technique.

Laboratory Tests

Blood samples obtained at the T1, T2, and T3 time points were centrifuged at 2000g for 10 min within 30 min of being collected, and the plasma was stored at -80°C until further analysis. TNF-α and IL-2 levels were measured with quantitative sandwich enzyme-linked immunosorbent assay (ELISA) kits (TNF, Assaypro, catalog number: ET2010-1; IL-2, eBioscience, catalog numbers: BMS221CE and BMS221TENCE). These kits showed no significant cross-reactivity or interference with other cytokines.

Statistical Analysis

SPSS version 17.0 for Windows was used for statistical analysis. Statistical analysis was estimated using the data from previous studies performed in our institution (5). One standard deviation was aimed for detecting a difference in pain scores. The study required at least 16 patients per group to have a power of 80% and type I error of 0.05. Demographic data were analyzed by Student’s t-test, and cytokine data were compared with the Mann-Whitney U test (between groups) and the Wilcoxon test (within groups). Data are expressed as mean±standard deviation (SD). Pain and sedation scores were analyzed with the Pearson’s chi-squared test (between groups) and the McNemar’s test (within groups). A p value of less than 0.05 was considered significant.

Results

There were no significant differences between the two groups in terms of age, weight, sex, and duration of anesthesia (Table 1), and the preinduction values of the two cytokines measured did not differ significantly between the two groups. The plasma levels of TNF-α in the Preempt EA group at T1, T2, and T3 were 29.2±15.0, 33.2±17.7, and 39.9±23.6 pg ml-1, respectively, whereas the plasma levels of TNF-α in the Postop EA group at T1, T2, and T3 were 29.8±8.2, 38.9±11.6, and 49.5±15.76 pg ml-1, respectively. TNF-α levels were significantly increased at T2 and T3 compared to T1 in both groups (Table 2a). The Postop EA group had significantly higher levels of TNF-α than the Preempt EA group at T2 and T3 (p=0.039 and p=0.023, respectively). In the Preempt EA group, TNF-α levels were significantly increased at T3 compared to T1 and T2, whereas in the Postop EA group, the TNF-α levels were significantly increased at T2 and T3 compared to T1 (Table 2b).

The plasma levels of IL-2 in the Preempt EA group at T1, T2, and T3 were 20.5±3.4, 19.9±3, and 20.6±3.4 pg ml-1, respectively, whereas the Postop EA group IL-2 levels at T1, T2, and T3 were 19.8±2.8, 17.8±2.1, and 16.5±1.8 pg ml-1, respectively (Table 3a). IL-2 values were significantly higher at T2 (p=0.005) and T3 (p=0.001) in the Preempt EA group than in the Postop EA group. There was a statistically significant decrease in IL-2 levels at T2 compared to T1 in the Preempt EA group. On the other hand, in the Postop EA group, the significant changes were also observed in IL-2 levels at T1, T2, and T3 (Table 3b).

Pain scores were divided into two groups (no pain: score between 0 and 2 and painful: score between 3 and 5), and there were no statistically significant differences found between the Preempt EA and Postop EA groups (Table 4a). The distribution of pain scores between the groups and within the groups are described in Table 4a, patients categorized by the time of the request for analgesia are described in Table 4b. There were no differences in postoperative sedation scores between the groups (Table 5).

Discussion

There have been many studies with different results on the effects of preemptive analgesia on pain scores and neurohumoral changes (4-6). However, these studies used different methods and drugs. The definition of preemptive analgesia refers in practice, the prevention of central sensitization caused by incisional and inflammatory injury through the preoperative, intraoperative, and postoperative periods. The initial analgesic dose starts before surgery and continues through the intraoperative and postoperative periods (7-10). Gottschalk et al. (11) compared a preemptive bolus of bupivacaine with a postoperative continuous epidural infusion of bupivacaine that began at the fascial closure in radical prostatectomy patients. They found that the preemptive group had better visual analog scale (VAS) scores during the first 4 postoperative days. A meta-analysis of eight studies that compared the presurgical versus postsurgical initiation of continuous epidural analgesia (including opioids, local anesthetics, and ketamine) in terms of pain relief for 24-72 h postoperatively showed that a preemptive epidural regimen offered no improvement in postoperative pain relief (8). Another meta-analysis of nine studies that compared the preincisional and postincisional continuous epidural infusion of a local anesthetic with or without opioid demonstrated significantly better VAS scores in only two of the reports. Three of the nine studies were on abdominal surgery, and one of them showed that preemptive administration led to a benefit in pain control (9). We did not find statistically significant differences between the two groups in pain scores at 1 h and 24 h after surgery, although we did observe that a higher percentage of patients in the preemptive group had better scores; 71% of patients in the preemptive group had a pain score between 0 and 2, whereas only 48.3% had these scores in the postoperative group. We thought the possible explanation is that preemptive analgesia may not yield the effects in young children as the central nervous system pathways to transmit, process, and respond to stimuli may be immature compared to that in adults. Ho et al. (12) compared preemptive and postoperative caudal blocks for outpatient urogenital surgery in children aged 1-6 years and did not find any difference. Furthermore, Holthusen et al. (13) could not demonstrate any differences when they compared the effects of preoperative and postoperative caudal blocks on pain in 25 children. Altintas et al. (14) compared the efficacy of presurgical versus postsurgical axillary blocks on postoperative pain in 49 children aged 1-11 years and observed that although facial pain scores were higher in the presurgical group than in the postsurgical group, both groups had effective analgesia, with pain scores of less than 2.

Surgical trauma induces peripheral nerve and tissue injury that leads to a local inflammatory reaction and elevated levels of proinflammatory cytokines that can induce peripheral and central nerve sensitization. Preemptive analgesia can suppress the nociceptive stimuli from an injured tissue to prevent the central sensitization (15). Furthermore, a continuous epidural infusion during the preoperative and postoperative periods may prevent central sensitization and also pain hypersensitivity due to the inhibition of acute inflammatory mediators in the postoperative period (9). Preemptive analgesia may produce a blockade of sufficient depth and duration to prevent the afferent transmission of noxious stim uli from the periphery to the central nervous system. Pain intensity measurement is one method to evaluate the effectiveness of analgesic treatment, and another is the detection of neurohumoral and inflammatory mediators. Nociceptive mediators and cytokines play important roles in the mechanism of acute pain (15). TNF--α is a proinflammatory cytokine and one of the early mediators of neuroinflammation and central pain sensitization (4). Both preoperative and postoperative epidural analgesia are important in controlling the immunological effects of surgery-induced stress. The production of proinflammatory cytokines, such as TNF-α may decrease when the afferent transmission of noxious stimuli is blocked (1,6). Moselli et al. (1) compared the proinflammatory responses (including cytokines) of two groups. The first group received a preoperative epidural infusion of levobupivacaine that continued through the postoperative period, whereas the second group received an infusion of remifentanyl perioperatively and an epidural infusion of levobupivacaine postoperatively. While the TNF-α levels did not change in the preemptive epidural analgesia group, postoperative increases in TNF-α levels were observed in the postoperative analgesia group. Akural et al. (16) did not find a significant difference in TNF-α levels between a group that received a preemptive epidural infusion of sufentanil and one that received sufentanil postoperatively.

IL-2 is an anti-inflammatory cytokine that is important in cell-mediated immunity. Theimmunosuppression after surgical incision results from T cell dysfunction, and impaired synthesis of IL-2 correlates with injury severity (17). In hysterectomy patients, Beilin et al. (4) observed lower IL-6 levels, reduced suppression of IL-2 levels, no significant changes in TNF-α levels, and better analgesia scores in those treated with preemptive analgesia compared to intravenous analgesia group. Yokoyama et al. (18) reported no differences in TNF-α levels and pain scores except at the end of surgery in radical esophagectomy patients given in preemptive analgesia group. Our study demonstrates significant increases in TNF-α levels in both the preemptive and postoperative epidural infusion groups, but the increase was more prominent in the postoperative group for at least 24 h after surgery. IL-2 levels were higher in the preemptive group, but there were no differences in the analgesic score. We believe that lower levels of TNF-α and the reduction in the suppression of IL-2 in the Preemp EA group compared to that in the Postop EA group demonstrate the preemptive effects of epidural infusion. It has been demonstrated that preemptive epidural infusion attenuates the suppression of the Th1 CD4+ T cells that secrete IL-2 (4).

In conclusion, the present study demonstrates that patients who received preemptive analgesia exhibited reduced proinflammatory but increased antiinflammatory cytokine levels and that sufficient analgesia was provided to both the preemptive and postoperative groups. We believe that although both the preemptive and postoperative epidural administration of a local anesthetic and an opioid seem to be fairly effective at blocking afferent nervous transmission and central sensitization and, can ensure adequate pain relief, only preemptive administration leads to a reduction in inflammatory mediators.

Address for Correspondence/Yazışma Adresi: Ayşe Çiğdem Tütüncü İstanbul University Faculty of Medicine, Anesthesiology and Reanimation, İstanbul, Turkey
E-mail: [email protected] Received/Geliş Tarihi: 26 April 2013 Accepted/Kabul Tarihi: 09 May 2013