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THE EFFECT OF PREEMPTIVE EPIDURAL ANALGESIA ON THE DYNAMICS OF THE PROINFLAMMATORY CYTOKINES LEVEL

IN LOWER EXTREMITY SURGERY Pengaruh Preemtif Epidural Analgesia terhadap Dinamika Kadar Sitokin Proinflamasi

pada Opersi Ekstremitas Bawah

Muhammad Ramli Ahmad Departement of Anestesiologist Faculty of Medicine Hasanuddin University Makassar

ABSTRAK

Kerusakan jaringan menimbulkan reaksi inflamasi lokal yang akan mengiringi peningkatan kadar sitokin proinflamasi seperti tumor necrosis factor alpha (TNF-α), Inteleukin-1β (IL-1β) dan Interleukin-6 (IL-6). Sitokin tersebut dapat menginduksi sensitisasi sistem saraf pusat dan perifer menimbulkan hiperalgesia. Adanya interaksi timbal balik antara sitokin proinflamasi dan nyeri dimana sitokin proinflamasi memodulasi sensitivitas nyeri, sedangkan nyeri mempengaruhi sintesis dan pelepasan sitokin. Akibat adanya umpan balik antara nosisepsi dan sitokin proinflamasi, maka tidak mustahil nyeri menyebabkan kadar sitokin proinflamasi jauh lebih tinggi..Preemtif epidural analgesia bertujuan untuk mencegah terbentuknya hipersensitifitas nyeri saat dan setelah operasi. Penelitian ini merupakan uji klinik tersamar ganda, mengikutsertakan 48 pasien (umur 20-60 tahun) yang menjalani pembedahan orthopedi tungkai bawah. Pengukuran kadar sitokin proinflamasi (TNF-α, IL-1β, IL-6) dilakukan sebelum induksi, pasca bedah dini, jam ke-4, -8, dan -24 pasca bedah. Sampel dibagi dua kelompok: Kelompok I (n=24) diberikan Bupivakain 0,25% 10 cc melalui epidural.. Kelompok II (n=24) diberikan NaCl 0,9% melalui epidural sebagai kelompok kontrol, dilanjutkan kontinyu 4 cc Bupivakain 0,25% sampai 24 jam pasca bedah. Setelah pemberian Bupivakain pada kelompok I dan NaCl 0,9 kelompok kontrol, semua pasien menjalani general anestesi sampai selesai. Setiap kelompok diperiksa kadar sitokin proinflamasi dan kadarnya dibandingkan sebelum perlakuan dengan pasca bedah dini jam ke-4, -8 dan -24 jam pasca bedah. Kelompok I (premptif epidural analgesia) memperlihatkan dinamika kadar sitokin proinflamasi lebih rendah dibandingkan kelompok II (kelomok kontrol), namun secara statistik tidak bermakna. Pada kelompok kontrol kadar sitokain proinflamasi meningkat tajam pada pasca bedah dini terutama TNF-α . Jika dibandingkan dengan kelompok preemptif secara statistik bermakna. Kadar IL-1β menurun pada kelompok preemtif dari semua waktu pengamatan. Disimpulkan bahwa pemberian analgesia preemtif epidural dapat menekan produksi sitokin proinflamasi.

Kata kunci: preemtif epidural, sitokin, TNF-α, Interleukin 1β, Interleukin 6.

ABSTRACT

Tissue damage will trigger a local inflammatory reaction that will accompany an increase in the level of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α), Interleukin-1β (-1β) and Interleukin-6 (IL-6). The cytokines can induce the sensitization of central and peripheral nervous system, resulting in hyperalgesia. There is a bidirectional interaction between proinflammatory cytokines and pain, in which proinflammatory cytokines modulate the sensitivity to pain, while pain influences the synthesis and release of the cytokines. Because of the feedback mechanism between nociception and proinflammatory cytokines, it is not impossible that pain may cause a considerable raise in the level of proinflammatory cytokines. The purpose of preemptive epidural analgesia is to prevent the development of pain hypersensitivity during and after surgery. The study is a double-blinded clinical trial that included 48 patients (age 20-60 years) that undergo orthopedic surgeries for lower extremity. The level of proinflammatory cytokines (TNF-α, IL-1β, IL-6) were measured before induction of anesthesia, in the early postoperative period, and at 4, 8, and 24 hours after surgery. The patients were divided into two groups: Group I (n=24) received 10 cc Bupivacaine 0,25% via epidural. Group II (n=24) received NaCl 0,9% via epidural as a control group, and continued with 4 cc bupivacaine 0,25% until 24 hours post operative After the administration of Bupivacaine to Group I and NaCl 0,9% to the control group, all patients were

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anesthetized with general anesthesia until the end of the procedure. Comparison was done between both groups for the level of proinflammatory cytokines, and also for the level of proinflammatory cytokines before the procedure and at 4, 8, and 24 hours after surgery. Group I (preemptive epidural analgesia group) showed less changes in the proinflammatory cytokines level compared with group II (control group), but the difference is not statistically significant. In control group, proinflammatory cytokines particularly TNF-α, increase dramatically on early post operative period. And statistically significant if compared to preemptive group. IL-1β level decrease in preemptive group within all course of observation period. In conclusion, administration of epidural preemptive analgesia can lower the production of proinflammatory cytokines.

Keywords: preemptive epidural, cytokines, TNF-α, Interleukin 1β, Interleukin 6

INTRODUCTION Preemptive analgesia is a procedure intended to minimize post operative pain by preventing the transmission of noxious stimuli caused by surgery to the central nervous system. The prevention must cover the entire duration of the noxious stimuli, starting from the beginning of noxious stimuli, so that the surgical trauma or inflammatory insults will not cause central nor peripheral sensitization. The tissue and peripheral nerve endings damaged by surgical trauma will be exposed to a number of substances released from the damaged tissue and to inflammatory mediators that will activate the nociceptors, such as prostaglandin, proton, serotonin, histamin, bradykinin, purin, cytokine, and neuropeptides that act on specific receptors at sensory neurons and have important interactions. The initial damage and inflammation causes the C and Aδ fibers to alter, and this alterations are referred to as sensitization. The next transmission is controlled by a modulation complex in the spinal cord. Some impuls passes through the cornu anterior and triggers a segmental reflex respons, while some other is transmitted at a higher level through the spinothalamic and spinoreticular tract and triggers suprasegmental and cortical responses. Tissue and peripheral nerve damage will bring about a local inflammatory reaction that will accompany an increase of the proinflammatory cytokines such as TNF-, Interleukin 1β (IL- β) and Interleukin 6 (IL-6). The cytokines will induce the

sensitization of peripheral and central nervous system, resulting in hyperalgesia. There is a bidirectional interaction between proinflammatory cytokines and pain, in which proinflammatory cytokines modulate the sentisization to pain, and pain stimulates the synthesis and the release of the cytokines. Because of the feedback mechanism between nociception and proinflammatory cytokines, it is not impossible that pain may cause a considerable raise in the the level of proinflammatory cytokines. Hyperalgesia may develop from the alterations in synaptic transmission and peripheral sensitization caused by inflammation, and the proinflammatory cytokines TNF-α, IL-1β, IL-6, and IL-8 have an important role in the nerve plasticity. Proinflammatory cytokines can indirectly modulate the nociception process during pain transmission by inducing the release of neuroactive substances, such as nitric oxide (NO), oxygen free radicals, prostaglandin and excitatory amino acids, from microglia and astrocytes. Yoshiyuki Naito et al found that there are no significant changes of TNF-α and IL-6 in patients receiving epidural analgesia for pancreatoduodenectomy, and this result is in accordance with the finding of Jeong-Yeon Hang that preemptive epidural analgesia cannot prevent the increase of the leukocytes. Tang Ceng et al showed that the administration of preemptive analgesia using clonidine via epidural will result in lower cytokine production compared with the group without preemptive.

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Meanwhile, C.P. Kuo et al published their results about the comparison between the effect of epidural thoracal anesthesia and intravenous lidocaine infusion toward the cytokine response and postoperative pain. From the results, they conclude that lidocaine administration via epidural before and after surgery results in a significant postoperative analgesia, and lower the production of proinflammatory cytokines. It is not known whether nerve block contributes to the decreased production of proinflammatory cytokines. This issue is still controversial with a number of parameters, so that we are interested to study the effect of preemptive epidural to the level of proinflammatory cytokines.

MATERIALS AND METHODS After obtaining an approval from the Ethical Committee of Medical and Health Study, Medical Faculty of Hasanuddin University, Makassar, subjects that met the inclusion criteria (age 20-60 years, body weight 40-70 kg, American Society of Anesthesiologists Physical Status ( ASA PS) 1-2, undergoing elective surgeries for lower extremity) were given informed consent as a study sample. Subjects were excluded if subject was not cooperative, has any contraindication for epidural, allergic to local anesthetic agent Bupivacaine, received blood transfusion during operation, and were consuming NSAID or corticosteroids. The general data (age, gender, bodyweight, height and ASA physical status) of the patients were recorded before the surgery. Afterward, patients were randomly divided into 2 groups: Group I (Preemptive): subjects were given Bupivacaine 0,5%, and Group II (Control): subjects were given NaCl 0,9%. The epidural catheter for each patient was placed at L1-L2 or L2-L3 interspace, and catheter was advanced 3-4 cm with cephalad direction. Test dose that consists of lidocaine 2% + adrenaline 1 :

200.000 was given to evaluate the location of epidural catheter and the possibility of intravascular placement. After the test dose, the local anesthetic agent, 10 ml bupivacaine 0,25% + adrenaline 1 : 200.000 was administered via the epidural catheter, followed by intermittent dosing of 6 ml bupivacaine 0,25%. Blood samples were taken before induction of anesthesia, in the early post operative period, 4, 8, and 24 hours post operatively for the measurements of TNF-α, IL-1β, and IL-6 levels. Measurements of TNF-α, IL-1β, and IL-6 levels were done using ELISA method (R&D System, Minneapolis, USA) in Prodia Laboratory Makassar and Jakarta. The standard range and detection limit for the kits are 0,5-32 pg/ml and 0,106 pg/ml for TNF-α, 0,125-8,00 pg/ml and 0,05 pg/ml for IL-1β, and 0,156-10.00 pg/ml and 0,039 pg/ml for IL-6, respectively. RESULTS This study was conducted from October 2009 to July 2010 in Wahidin Sudirohusodo Hospital, Makassar. The study included 50 patients, two patients were excluded because of prolonged duration of surgery and re-operation. There were 48 subjects that were included until the end of the observation, consisted of 24 subjects in the preemptive analgesia group and 24 subjects in the control group. There were no significant differences between the treatment group (preemptive epidural) and the control group regarding age, weight, height, and gender (Table 1). Serum level of TNFα Table 2. And Figure 1 shows the dynamics of TNFα levels before incision and postoperatively, and it shows a greater change in TNFα levels in the control group at each observation time, although it is not statistically significant (p>0.05).

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Table 1. Characteristics of the study sample subjects

Characteristics Preemptive group Control Group P value Gender Male Female

18 6

16 8

0.53

Age (Years) 32.33 ± 11.23 28.96 ± 13.58 0.53 Weight (kg) 61.92 ± 10.41 58.29 ± 6.39 0.15 Height (cm) 164.00 ± 8.80 163.71 ± 5.14 0.89 Duration of surgery (minutes)

150.42±48.94 153.13±45.22 0.84

Data are expressed as mean ± standard deviation and were tested using independent t-test. *Tested using Pearson chi square. #Tested using Mann Whitney-U test. p value <0.05 is considered significant. Table 2. Serum level of TNFα

Time (Hour) Epidural Preemptive Group( pg/ml)

Control Group ( pg/ml)

P value

Before incision 3.13±2.48 3.91±3.30 0.42 Early post operative 3.27±4.59 8.09±11.29 0.08 Post operative, hour-4 4.00±5.81 7.22±9.20 0.39 Post operative, hour-8 3.69±5.78 4.39±4.65 0.34 Post operative, hour-24

4.96±6.22 6.99±7.55 0.18

Data are expressed as mean ± standard deviation and were tested using Mann Whitney-U test. p value <0.05 is considered significant.

Figure 1. TNFα levels before incision to 24 hours postoperative

1234567891011121314151617181920212223242526272829303132

0.42 0.08 0.39 0.34 0.18

TNF

-α (p

g/m

l)

Waktu (Pre Op dan Pasca Bedah, Jam Ke-)

Kelompok Epidural Preemtif

Nilai p

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In Table 3, it is shown that the difference between postoperative and pre-incisional levels of TNFα is greater in the control group at hour-0, hour-4, and hour-24. The difference is statistically significant (p<0,05) at hour-0 (early postoperative period). Table 4 and Figure 2 shows the dynamics of IL-1β levels before incision and postoperatively, and it shows a greater change in Interleukin 1β levels in the control group at each observation time postoperatively, although it is not statistically significant (p>0.05). Table 5 shows a decrease in IL-1β level at each observation time in the preemptive epidural group, while the

opposite was found in the control group. However, the difference is not statistically significant (p>0.05). If each group is evaluated separately (Table 6), we can see that in the epidural group, at all observation times, the Interleukin 1β levels were lower than the level before incision. The decrease was significant at the early postoperative period, hour-8, and hour-24. The opposite was found in the control group, in which an increase in IL-1β level was observed at all observation periods, although it is not significant (p>0.05).

Table 3. The Difference between the postoperative and pre-incisional level of TNFα.

Time Epidural Preemptive Group

Control Group

P value

Before incision

and Early postoperative

0,14 4.18 0.03

Before incision

and Post operative, hour-4

0.87 3.31 0.25

Before incision

and Post operative, hour-8

0.56 0.48 0.95

Before incision

and Post operative, hour-24

1.83 3.08 0.32

Data are expressed as mean ± standard deviation and were tested using Mann Whitney-U test. p value <0.05 is considered significant.

Serum level of Interleukin 1β Table 4. Serum level of Interleukin 1β

Time Epidural Preemptive Group (pg/ml)

Control Group (pg/ml)

P value

Before incision 1,93±2.47 1.99±2.18 0.77 Early post operative 1.69±2.55 2.20±2.72 0.64 Post operative, hour-4 1.89±2.39 3.03±3.11 0.38 Post operative, hour-8 1.46±2.32 2.03±2.82 0.36 Post operative, hour-24

1.45±2.20 2.03±2.34 0.09

Data are expressed as mean ± standard deviation and were tested using Mann Whitney-U test. p value <0.05 is considered significant.

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Figure 2. Interleukin 1β levels before incision to 24 hours postoperative

Table 5. The Difference between the postoperative and pre-incisional level of IL-1β

Time Epidural Preemptive Group

Control Group

P value

Before incision

And Early postoperative -0.24 0.21 0.15

Before incision

and Post operative, hour-4

-0.04 1.04 0.10

Before incision

and Post operative, hour-8

-0.47 0.04 0.08

Before incision

and Post operative, hour-24

-0.48 0.04 0.51

Data are expressed as mean ± standard deviation and were tested using Mann Whitney-U test. p value <0.05 is considered significant.

Table 6. The Difference between postoperative and pre-incisional level of Interleukin 1β in each group

Time Epidural Preemptive Group

Control Group

Difference P value Difference P value Before incision

And Early postoperative

-0.24 0.01 0.21 0.78

Before incision

and Post operative, hour-4

-0.04 0.37 1.04 0.11

Before incision

and Post operative, hour-8

-0.47 0.00 0.04 0.81

Before incision

and Post operative, hour-24

-0.48 0.01 0.04 0.71

Data were tested using Wilcoxon Signed Rank Test. p value < 0.05 is considered significant.

0.001.002.003.004.005.006.007.008.00

0.77 0.64 0.38 0.36 0.09

Pre op 0 4 8 24

Inte

rleuk

in 1

β (p

g/m

l)

Waktu (Pre Op dan Pasca Bedah, Jam Ke-)

Kelompok Epidural Preemtif

Nilai p

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Serum level of Interleukin-6 Table 7 and Figure 3 shows the dynamics of Interleukin-6 levels, and it shows a greater change of Interleukin-6 levels in the control group, although it is not statistically significant (p>0.05). The level of this inflammatory cytokine was

clearly increased (p>0,05) in posto-perative periods in both groups. Table 8 shows that the difference between the level of cytokine IL-6 before and after incision is higher in the control group at all observation times, although it is not significant (p>0,05).

Table 7. Interleukin-6 levels

Time Epidural Preemptive Group (pg/ml)

Control Group ( pg/ml)

P value

Before incision 3.33±2.08 3.11±2.04 0.70 Early post operative 17.22±6.62 19.06±5.63 0.24 Post operative, hour-4 20.18±4.53 20.97±2.98 0.75 Post operative, hour-8 20.62±5.64 21.53±2.57 0.84 Post operative, hour-24

21.18±4.33 22.46±2.47 0.42

Data are expressed as mean ± standard deviation and were tested using Mann Whitney-U test. p value <0.05 is considered significant.

Figure 3. Interleukin-6 levels before incision to 24 hours postoperative

0.001.002.003.004.005.006.007.008.009.00

10.0011.0012.0013.0014.0015.0016.0017.0018.0019.0020.0021.0022.0023.0024.0025.0026.0027.00

0.70 0.24 0.75 0.84 0.42

Pre op 0 4 8 24

Inte

rleuk

in-6

(pg/

ml)

Waktu (Pre Op dan Pasca Bedah, Jam Ke-)

Kelompok Epidural Preemtif

Kelompok Kontrol

Nilai p

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Table 8. The Difference between the postoperative and pre-incisional level of IL-6.

Time Epidural Preemptive Group

Control Group

P value

Before incision

And Early postoperative

13.89 15.96 0.19

Before incision

and Post operative, hour-4

16.86 17.86 0.88

Before incision

and Post operative, hour-8

17.29 18.42 0.97

Before incision

and Post operative, hour-24

17.85 19.35 0.35

Data are expressed as mean ± standard deviation and were tested using Mann Whitney-U test. p value <0.05 is considered significant.

Table 9. The Difference between the postoperative and pre-incisional level of Interleukin 6 In Each Group.

Time Epidural Preemptive Group

Control Group

Difference P value Difference P value Before incision

And Early postoperative

13.89 0.00 15.95 0.00

Before incision

and Post operative, hour-4

16.86 0.00 17.86 0.00

Before incision

and Post operative, hour-8

17.29 0.00 18.42 0.00

Before incision

and Post operative, hour-24

17.85 0.00 19.35 0.00

Data were tested using Wilcoxon Signed Rank test. p value <0.05 is considered significant.

From the evaluation of the difference of IL-6 levels before and after incision in each groups (Table 9), it is seen that the control group showed a greater difference of IL-6 levels compared with the epidural group, at all observation times. The increase from the pre-incisional level to the post-incisional level is considerably significant (p<0,01) in each group.

DISCUSSION The generation of pain is a result of the communication between immune system and the brain, indicated by the secretion

of proinflammatory mediator cytokines by activated immune cells. Studies show a bidirectional interaction between proinflammatory cytokines and pain, in which the proinflammatory cytokines modulate the sensitization to pain, whilst pain affect the synthesis and the release of the cytokines.

Some recent studies emphasize on the relationship of pain and the immune system, since the discovery of inflammatory mediators such as TNF alpha, IL-1, IL-6, NGF and prostaglandin

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E2 in inflammatory exudate. These mediators can generate pain in the form of hyperalgesia. In animal experiment, hyperalgesia can be induced by the injection of lipopolisaccharide into the peritoneum, which in turn will stimulate macrophages to secrete proinflammatory cytokines.

The serum level of TNFα The pre-incisional and post operative levels of TNFα at each observation were apparently higher in the control group, even though it is not significant, in accordance with earlier studies that compared the patient controlled epidural analgesia (PCEA) group in the postoperative period with a group that received preemptive epidural followed by PCEA (PA + PCEA), and studies that compared the levels of TNFα cytokine in patients receiving neuraxial anesthesia with patients receiving general anesthesia. In fact, several studies shows an increase in the level of TNF α measured in the injured area and the peritoneal fluid, but there was no change in TNFα level in the circulation during perioperative period. So far, it is believed that TNFα level in the injured area is always higher than its plasma level, because this cytokine is mainly produced by the injured cells (Wu CT et al, 2004). A study by Benzoin found that the maximum release of TNFα occurs before 24 hours. This is in agreement with our study, in which the dynamics of the increase in TNF α levels at 4, 8, and 24 hours postoperatively was lower in the preeemptive group compared with the control group, although the difference was not statistically significant. Ching-Tang Wu found that preemptive epidural analgesia with clonidine showed no difference in the changes of TNFα levels during the observation period compared with the control group, and there was no significant difference. Our results showed an increase in TNFα level after incision compared with before incision, and the increase was about 3

times higher in the control group, and the difference was significant compared with the the epidural group in early postoperative period. This indicated that epidural bupivacaine can modulate the increase of cytokine TNFα, and this modulation results from the anti-inflammatory effect of local anesthetics. A study by Chi-Yuan LI showed that lidocaine inhibits the secretion of MCP-1 by human monocyte, and supresses the LPS-induced production of MCP-1 mRNA. The knowledge about the effect of lidocaine on MCP-1 (Chemokine) is important to understand the interaction between local anesthetic agents and wound healing. The role of lidocaine around the surgical wound is to reduce leucocyte migration and the metabolic activation in the wound area. After local administration or infiltration, the tissue concentration of lidocaine is usually found in the range of milimolars, and the same concentration is found around the spinal nerve or spine after epidural administration of lidocaine. Lidocaine prevents the adhesion of granulocyte and the migration of granulocyte to inflammation site. The same property is also found in the members of amide local anesthetic class such as bupivacaine. R Sinclair found that amide local anesthetics and bupivacaine inhibit the release of LTB4, a leucoattractant of monocytes and macrophages.

1. The serum level of Interleukin-1β A study by Beilin compared the effect of several postoperative pain management techniques on postoperative immune function. This is done by observing the production of IL-1β, IL-2, IL-6 and NKC cytotoxicity, and also the lymphocytic mitogenic response. The technique used in the study was intermittent opioid regiment (IOR), PCA, and PCEA. The result showed that the mitogenic response were lowered in all groups in the first 24 hours and returned to the preoperative value within 72 hours in the PCEA group, but

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remained low in the PCA group. The production of IL-1β and IL-6 were increased in the IOR and PCA groups, while in the PCEA group it remained almost unchanged. In the PCEA group that received the combination of opioid and local anesthetics, there were a suppresion in lymphocyte proliferation and a reduced response of proin-flammatory cytokines in the posto-perative period.

In this study, a lower level of IL-1β was found after administration of preemptive epidural compared with the control group, but unfortunately the result was not significant. However, after the change of IL-1β level before incision and after incision was observed, it was apparent that the level of IL-1β was lower after incision compared with before incision, and the change was significant at hour-0, 8, and 24. This results shows that preemptive epidural can prevent a surge, and even can reduce the level of IL-1β, a proinflammatory cytokine. The study is in accordance with the study by Beilin, in which an increase in the level of IL-1β was found in patients receiving intravenous posto-perative analgesia (according to the patients’ need) and patients receiving PCA. The increase in the level of cytokine IL-1β was not found in patients receiving PCEA postoperatively. The administration of preemptive epidural is intended to prevent central sensitization, and it is also expected to decrease the level of IL-1β. In this study, it was apparent that IL-1β level was lower in the preemptive epidural group compared with the control group, although the difference was insignificant. Besides, after measuring the difference of the postoperative and the pre-incisional levels, it was clearly seen that there was a reduction in the IL-1β level in the preemptive epidural group, either when the two groups were compared or when each group were evaluated individually. From this result, it can be concluded that preemptive epidural can modulate the

increase of IL-1β, and even can suppress the release of this proinflammatory cytokine. This result has never been found in earlier studies, and proves that bupivacaine has an anti-inflammatory property. A study by R Sinclair suggested that amide local anesthetics has a suppressing effect on the metabolic activation and the secretory function of leukocyte stimulated by a number of agonists. Lidocaine was reported to inhibit the release of leukotriene B4 and interleukin (IL)-1 from human leukocyte and stop the release of tumor necrosis factor (TNF) and IL-1 in the lung bronchoalveolar lavage fluid caused by endotoxin from a wound. Taniguchi et al found that lidocaine has an inhibitory effect on the production of IL-6 and IL-8 in an experiment, in which endotoxin was administered to rabbits. There are growing evidences that suggest that lidocaine and bupivacaine have a direct effect on the protein-coupled G receptors, such as lysophosphatidic acid receptor that is involved in the activation of platelet, inflammation and wound healing, and tromboxane receptor that is involved in plateled aggregation and the release of granule contents.

The serum level of Interleukin-6 Interleukin-6 is the main proinflammatory cytokine that is produced immediately after (2-4 hours) tissue injury, and is the major stimulus of acute phase response. A vast amount of Interleukin-6 released from the surgical wound into the circulation will measure in a concentration equivalent to the degree of surgical insult. Cruickshank et al themselves reported that the level of IL-6 is affected by the degree of tissue injury, and not by the duration of the insult. Recent study showes that after an elective procedure, IL-6 remains elevated for 48-72 hours. Furthermore, IL-6 can induce central and peripheral sensitization that finally will result in hyperalgesia. Several studies reported that the level of IL-6 will

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increase after nerve injury, both peripheral and central nerves, and therefore has a role in the development of hyperalgesia via direct effect to spinal nociceptive or glial activation in animal studies. Yokoyama et al suggested that interleukin-6 is increased in postoperative period, whether the patient receive preemptive epidural or general anesthesia. In the other hand, Kuo CP et al suggested that lidocaine via epidural or intravenous can reduce the increase of IL-6 until it reach the preoperative level after 24 hours postoperatively. Beilin B also proved that with the administration of the combination of 12cc bupivacaine 0,5% and fentanyl 50-100 ug as preemptive epidural, the level of IL-6 and IL-1β are significantly lower than if the combination is given via PCEA. Beilin B et all showed that IL-6 level was increased, but the increase in the PCEA group is less than in the PCA group, and the IL-6 level almost returned to normal after 72 hour postoperatively. This study is consistent with earlier studies investigating IL-6. The proinflammatory cytokine level is greatly increased after incision, both in the preemptive epidural group and the control group. In this study, it was also found that the dynamics of IL-6 level was lower in the epidural group. In the end of the observation (hour-24), the IL-6 level did not reach the pre-operative level, and this is similar with the earlier studies. IL-6 was not found returning to the control value, possibly because the observation in this study was not continued until 72 hours postoperatively. From the evaluation of the difference and the comparison between the posto-perative and preoperative levels of IL-6, it is found that the IL-6 level was higher in the control group. This results suggested that the use of epidural can modulate the increase of IL-6 better than without epidural. No difference in IL-6 level was found between the patients undergoing hysterectomy under general anesthesia

and patients receiving a combination of epidural and general anesthesia (Moore 1994). Different techniques of general anesthesia for hysterectomy procedure were applied to evaluate the effect on cytokine level, and the administration of propofol and alfentanil has a better association with decreasing serum level of IL-6 compared with general anesthesia using isoflurane. However, it has been reported that in abdominal hysterectomy procedure, the IL-6 level was increased in the same manner after the administration of 3 or 15 mcg/kgBB fentanyl.

CONCLUSIONS AND SUGGESTIONS Conclusions 1. The dynamics of TNFα, Interleukin-

1β and interleukin-6 were less increased in the preemptive analgesia group compared with the group without preemptive analgesia.

2. Interleukin-6 is increased after surgical trauma, and is not preventable by preemptive epidural.

3. Interleukin-1β (IL-1β) seems to have an important role on postoperative pain, and can be stabilized by preemptive epidural analgesia.

Suggestions 1. A routine protocol should be

established for the administration of preemptive analgesia for elective and emergency surgeries if there are no contraindications for epidural analgesia.

2. Further studies are needed to investigate the cytokines, particularly cytokines that have strong associations with pain, such as Intelukin 2 and Interleukin 8.

3. Further studies are needed for the administration of balanced preemptive analgesia using the combination of IV NSAID and preemptive epidural analgesia with local anesthetics.

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LITERATURE Gottschalk A & Smith SD. New

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Cousins MJ. Acute Pain Service. In Acute Pain Management: Scientific Evidence. Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine. Second Edition. 2005; 34-6.

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