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A comparison of the effect of total intravenous anaesthesia with propofol and remifentanil and inhalational anaesthesia with isoflurane on the release of pro- and anti-inflammatory cytokines in patients undergoing open cholecystectomy.



SUMMARY

The aim of the study was to investigate the effects of two anaesthetic techniques (total intravenous technique vs. inhalational technique) on changes in pro- and anti-inflammatory cytokine levels during open cholecystectomy Cholecystectomy Definition

A cholecystectomy is the surgical removal of the gallbladder. The two basic types of this procedure are open cholecystectomy and the laparoscopic approach.
. Forty ASA Asa (ā`sə), in the Bible, king of Judah, son and successor of Abijah. He was a good king, zealous in his extirpation of idols. When Baasha of Israel took Ramah (a few miles N of Jerusalem), Asa bought the help of Benhadad of Damascus and  PS I-II patients undergoing open cholecystectomy were randomly assigned to two groups. Group R received total intravenous anaesthesia with propofol and remifentanil and group F received balanced inhalational anaesthesia with isoflurane. The plasma levels of tumour necrosis factor-a (TNF-[alpha]), interleukin IL-6 and interleukin IL-10 were measured during and after surgery.

The pro-inflammatory cytokine levels (TNF-[alpha] and IL-6) and the anti-inflammatory cytokine (IL-10) showed a significant increase in their concentrations compared with pre-induction levels in both groups (P <0.05). By the end of anaesthesia and surgery, TNF-[alpha] and IL-6 were significantly lower in group R than in group F (P <0.05). At the end of anaesthesia and 12 hours postoperatively, IL-10 levels in group R were higher than in group F (P <0.05). These findings suggest that total intravenous anaesthesia using propofol and remifentanil suppresses the inflammatory response caused by surgery to a greater extent than a balanced inhalation technique using isoflurane.

Key Words: total intravenous anaesthesia, propofol, remifentanil, tumour necrosis factor-a, interleukin-6, interleukin-10

**********

Any surgical procedure impairs homeostasis homeostasis

Any self-regulating process by which a biological or mechanical system maintains stability while adjusting to changing conditions. Systems in dynamic equilibrium reach a balance in which internal change continuously compensates for external change in a feedback
 and triggers various haemodynamic, metabolic and immunologic reactions, (1,2). Results of many experimental and clinical studies have found that surgical trauma is associated with an impaired immune response in the postoperative period, which may be connected with altered production of pro-inflammatory cytokines, as well as inhibition of cellular responses (3). It has also been shown that proinflammatory and anti-inflammatory cytokines are pivotal for the acute-phase inflammatory and immunologic response induced after surgical trauma. The most important cytokines in this regard are tumour necrosis factor-[alpha] (TNF-[alpha]), interleukin IL-6 and interleukin IL-10 (4,5).

Anaesthesia itself may also alter immune function with potential impact on the postoperative course. General anaesthesia accompanied by surgical stress may influence the inflammatory responses that are essential for maintaining the homeostatic homeostatic

pertaining to homeostasis.
 state during the postoperative course (6). Various anaesthetics have been suspected of impairing various functions of the immune system either directly, by disturbing the functions of immune-competent cells, or indirectly by modulating the stress response (7,8). Different anaesthetic methods may interfere with the stress response, especially cytokine activation during and after surgery.

The aim of this study was to evaluate possible differences in the plasma cytokine response of TNF-[alpha], IL-6 and IL-10 with two anaesthetic techniques--total intravenous anaesthesia (TIVA TIVA Total Intravenous Anesthesia
TIVA Technician Information Verifying Agency (American Association of Veterinary State Boards)
TIVA Thermal Induced Voltage Alteration (defect analysis for integrated circuits) 
) using propofol/remifentanil versus balanced inhalational anaesthesia using isoflurane, in open cholecystectomy.

METHODS

After approval by the local ethics committee and written informed consent, 40 patients (ASA physical status I-II) undergoing open cholecystectomy were randomised Adj. 1. randomised - set up or distributed in a deliberately random way
randomized

irregular - contrary to rule or accepted order or general practice; "irregular hiring practices"
 to receive either TIVA with propofol and remifentanil (group R, n=20) or with isoflurane and fentanyl fentanyl /fen·ta·nyl/ (fen´tah-nil) an opioid analgesic; the citrate salt is used as an adjunct to anesthesia, in the induction and maintenance of anesthesia, in combination with droperidol (or similar agent) as a neuroleptanalgesic, and  (group F, n=20). Exclusion criteria were as follows: immune system disorders, major systemic illness known to alter inflammatory changes such as rheumatoid arthritis, and steroid medication within the past six months.

After the insertion of a peripheral IV cannula cannula /can·nu·la/ (kan´u-lah) a tube for insertion into a vessel, duct, or cavity; during insertion its lumen is usually occupied by a trocar.

can·nu·la or can·u·la
n. pl.
, anaesthesia was induced with remifentanil (0.5 [micro]g/kg/min) and propofol (6 mg/kg/h) in group R, and with fentanyl (3 [micro]g/kg) and propofol (2 to 3 mg/kg) in group E. In both groups, muscle relaxation was achieved with vecuronium (0.15 mg/kg) and tracheal tracheal

pertaining to or emanating from trachea.


tracheal aspiration
see transtracheal aspiration.

tracheal band sign
on contrast radiography of a dilated esophagus, the impression made ventrally by the trachea.
 intubation intubation /in·tu·ba·tion/ (in?too-ba´shun) the insertion of a tube into a body canal or hollow organ, as into the trachea.

endotracheal intubation
 was performed using an endotracheal tube. The cuff was inflated with 10 ml of air. After endotracheal intubation, the infusion rate of propofol was decreased to 3 mg/kg/h and another infusion of remifentanil (0.25 [micro]g/kg/min) was started in group R. To achieve similar depth of anaesthesia, BIS monitoring (Monitor Model A-2000[TM], Aspect Medical Systems Inc) was used targeting values between 40 and 50 intraoperatively. Increases in BIS-levels >50 were treated by increasing, first, the isoflurane concentration (up to 1.2 MAC) and second, by a bolus of fentanyl (1 [micro]g/kg) in group F and in group R, by an increase first in propofol infusion rate (max 6 mg/kg/h) and second in the remifentanil infusion rate (max 0.35 [micro]g/kg/min). Muscle relaxation was supplemented with vecuronium 0.05 mg/kg as required. The lungs of the patients were ventilated using a pressure-controlled mode with a maximum pressure of 20 cm[H.sub.2]0 and a positive end-expiratory pressure positive end-expiratory pressure
n. Abbr. PEEP
A technique used in respiratory therapy in which pressure is maintained in the airway so that the lungs empty less completely in expiration.
 (PEEP) of 5 cm[H.sub.2]O. Ventilation rate and maximum airway pressure were adjusted to maintain a normal end-tidal C[O.sub.2] (33 to 43 mmHg). Monitoring included continuous measurement of arterial blood pressure (mean arterial pressure The mean arterial pressure (MAP) is a term used in medicine to describe a notional average blood pressure in an individual. It is defined as the average arterial pressure during a single cardiac cycle. Calculation  [MAP]), heart rate (HR) and oxygen saturation (pulse oximetry). Hypotension hypotension
 or low blood pressure

Condition in which blood pressure is abnormally low. It may result from reduced blood volume (e.g., from heavy bleeding or plasma loss after severe burns) or increased blood-vessel capacity (e.g., in syncope).
 (MAP <60 mmHg) was corrected with either fluid administration (lactated Ringer's solution lactated Ringer's solution
n.
A solution containing sodium chloride, potassium chloride, calcium chloride, and sodium lactate in distilled water, used for the same purposes as Ringer's solution.
, hydroxyethyl starch solution) or a small bolus of ephedrine ephedrine (ĭfĕd`rĭn, ĕf`ĭdrēn'), drug derived from plants of the genus Ephedra (see Pinophyta), most commonly used to prevent mild or moderate attacks of bronchial asthma. .

Blood samples were drawn immediately before induction of anaesthesia ([T.sub.1]), at the end of anaesthesia and surgery ([T.sub.2]) and 12 hours postoperatively ([T.sub.3]). Blood samples (10 ml each) from all tested patients were drawn via an indwelling catheter inserted into a forearm vein and collected in heparinised syringes. After centrifugation of the blood at 3000 rpm for 10 minutes at 4[degrees]C, separated plasma samples were stored in two or three aliquots (120[micro]l) at -70[degrees]C until cytokine assay.

Using commercially available kits (Opt-EIA; Pharmingen, San Diego, CA, U.S.A.), plasma levels of TNF-[alpha], IL-6 and IL-10 were measured by a two-step sandwich enzyme-linked immunosorbent assay enzyme-linked immunosorbent assay
n.
ELISA.


Enzyme-linked immunosorbent assay (ELISA)
A diagnostic blood test used to screen patients for AIDS or other viruses.
 method, according to the manufacturer's instructions. Standards and samples were pipetted into the wells of a microtitre plate, which are precoated with specific cytokine antibodies. Cytokines are bound by the immobilised antibody. After washing away any unbound substances, an enzyme-linked polyclonal antibody specific for a cytokine is added to the wells. After a wash to remove any unbound antibody enzyme reagent, tetramethylbenzidine is added to the wells. The enzyme reaction yields a blue product, which turns yellow when the stop solution sulphuric acid is added. The optical density measured is in proportion to the amount of cytokine bound in the initial step. The sample values are then interpolated into the standard curve.

Statistical analysis

Analysis of variance for repeated measurements was used to compare the changes in values achieved at different intervals and to compare the difference between groups. Statistical analysis was undertaken with SPSS A statistical package from SPSS, Inc., Chicago (www.spss.com) that runs on PCs, most mainframes and minis and is used extensively in marketing research. It provides over 50 statistical processes, including regression analysis, correlation and analysis of variance.  11.5 (SPSS, Inc., Chicago, IL, U.S.A.) and P < 0.05 was considered statistically significant.

RESULTS

Patient groups were similar with regard to age, weight, gender, duration of anaesthesia and transfusion requirement. All values are expressed as mean [+ or -] SD (Table 1).

Pre-induction values of the pro-inflammatory cytokine levels (TNF-[alpha] and IL-6) and the anti-inflammatory cytokine (IL-10) did not differ significantly between the two groups. By the end of anaesthesia and surgery, TNF-[alpha] and IL-6 showed a significant change in their concentrations (P <0.05, Table 2). By 12 hours postoperatively, their values were still higher than the pre-induction level (P <0.05, Table 2). Also, the anti-inflammatory cytokine (IL-10) in both groups was increased significantly (P <0.05, Table 2) by the end of anaesthesia and surgery compared with the pre-induction level. It was then decreased at 12 hours postoperatively compared with the end of anaesthesia and surgery to reach a value above the pre-induction level (Table 2).

By the end of anaesthesia and surgery, TNF-[alpha] and IL-6 concentrations were significantly lower in group R (101[+ or -]20, 3.5[+or -]3.4 pg/ml) than in group F (164[+ or -]23, 18.7[+ or -]6.1 pg/ml, P <0.05, Table 2). At 12 hours postoperatively, the two cytokine levels appeared slightly higher in group F (132[+ or -]19, 15.5[+ or -]5.2 pg/ml) than in group R (98[+ or -]17, 13.7[+ or -]4.5 pg/ml), but the differences were not significant (Table 2). The IL-10 concentrations at the end of anaesthesia and surgery and 12 hours postoperatively in group R were higher than in group F (P <0.05, Table 2).

DISCUSSION

Major surgery causes a variety of physiological changes that are known collectively as the 'stress response' to surgery (1,2). The systemic inflammatory response during and after surgery is important in the development of postoperative complications. Severe dysregulation of the inflammatory process may provoke or aggravate postoperative complications, e.g. increased susceptibility to infections, inadequate stress reactions and hypercatabolism. Furthermore, the inflammatory cytokine response may exert a profound impact on the circulatory stability. Cytokines play a central role in the acute inflammatory and immune response initiated by trauma or infection (4,5).

Cytokines are a heterogeneous group of proteins which orchestrate the inflammatory response after surgery (9). The pro-inflammatory cytokines (IL-1, IL-6 and TNF-[alpha]) and the anti-inflammatory cytokines (IL-4 and IL-10) have local and systemic effects, which attempt to limit injury and the spread of infection, and provide a suitable environment for tissue healing and repair (10,11). The current study showed that the cytokine response to open cholecystectomy influenced both the pro-inflammatory (TNF-[alpha] and IL-6) and anti-inflammatory (IL-10) components.

TNF-[alpha] is thought to be the 'hub of the cytokine network', which is a critical early mediator in the genesis of a systemic inflammatory response. In addition to stimulating the production of secondary cytokines, such as the pro-inflammatory interleukin-6 and the anti-inflammatory interleukin-10, TNF-[alpha] is a primary inflammatory mediator that is responsible for many physiological changes such as hypotension, fever, tachycardia, oliguria oliguria /ol·i·gu·ria/ (ol?i-gu´re-ah) diminished urine production and excretion in relation to fluid intake.oligu´ric

ol·i·gu·ri·a
n.
Abnormally slight or infrequent urination.
 and changes in consciousness in patients with septic shock (12,13). Overproduction o·ver·pro·duce  
tr.v. o·ver·pro·duced, o·ver·pro·duc·ing, o·ver·pro·duc·es
To produce in excess of need or demand.



o
 of TNF-[alpha] can be disastrous to the host and is seen in such pathological conditions as autoimmune disorders and septic shock (14,15).

Interleukin-6 is a multi-potent cytokine produced in the course of inflammation (16). In addition to its role in the inflammatory response, it is important in host defence, immune responses and haematopoiesis hematopoiesis, haematopoiesis
the formation of blood. — hematopoietic, haematopoietic, adj.
See also: Blood and Blood Vessels

Noun 1.
. Interleukin-6 is critical to the development of acute-phase response during inflammation and has been demonstrated to be necessary for the final stages of plasma cell development as well as participating in a number of other processes (17-19). It has been reported that the IL-6 concentration in peripheral vein blood increases rapidly after abdominal surgery and the IL-6 response to surgery reflects the extent of tissue damage (20).

Interleukin-10 is associated with immunosuppressive Immunosuppressive
Any agent that suppresses the immune response of an individual.

Mentioned in: Antirheumatic Drugs, Graft-vs.-Host Disease, Immunosuppressant Drugs


immunosuppressive

1. pertaining to or inducing immunosuppression.

2.
 responses (21). Interleukin-10 is a well-characterised cytokine produced by Th2 cells and has been shown to have predominately anti-inflammatory effects. This cytokine inhibits the production of IFN-y by lymphocytes, TNF-[alpha] and IL-6 by macrophages and monocytes, and TNF-[alpha] and granulocyte-macrophage colony-stimulating factor granulocyte-macrophage colony-stimulating factor
n.
A naturally occurring protein that stimulates the production of granulocytes and macrophages by stem cells and is used as a drug by some immunosuppressed individuals.
 production by eosinophils. IL-10 is thought to be important in modulating multiple aspects of the Th2 response to certain parasitic infections. In IL-10 gene-deficient mice an overproduction of inflammatory cytokines and development of chronic inflammatory diseases have been shown (22,23).

Changes in the cytokines levels caused by surgical trauma are believed to influence local cellular immune response cellular immune response
n.
See cell-mediated immune response.
 within the peritoneum peritoneum (pĕrətənē`əm), multilayered membrane which lines the abdominal cavity, and supports and covers the organs within it. The part of the membrane that lines the abdominal cavity is called the parietal peritoneum. . During that immunologic response several cells and mediators are engaged, both to eliminate infectious agents and remove and repair damaged tissues. The above-mentioned reactions are balanced by anti-inflammatory mechanisms that are responsible for the restoration of homeostasis and proper functioning of the afflicted tissues and organs. Regaining the correct function by the particular tissues and organs also depends on the delicate balance between the mediators of pro-inflammatory and anti-inflammatory mechanisms. Furthermore, increased levels of pro-inflammatory cytokines after major surgical procedures have been connected with increase in postoperative complications and morbidity (24,25). In the present study, elevated levels of TNF-[alpha] and IL-6 were demonstrated throughout the study period. At the same time, increased levels of the anti-inflammatory cytokine IL-10 were also observed. It is possible that the increased release of IL-10 observed after surgery plays a protective role during infection and trauma.

Our findings indicate that the choice of anaesthetic technique appears to affect the release of cytokines. Recently it has been shown both in vitro and in vivo that several intravenous anaesthetic agents have anti-inflammatory effects. Ketamine ketamine /keta·mine/ (ke´tah-men) a rapid-acting general anesthetic, used as the hydrochloride salt.

ke·ta·mine
n.
 prevents the pro-inflammatory cytokine (TNF-[alpha], IL-1 and IL-6) responses to endotoxemia in vivo (26). Moreover, thiopentone thiopental, thiopentone

a thiobarbiturate used extensively as a short-acting general anesthetic, administered by intravenous injection. Used as the sodium salt.
, etomidate and propofol increase IL-10 concentrations in LPS-induced cultured human whole blood (27).

Remifentanil is a recently introduced, esterase-metabolised synthetic opioid with an extremely short duration of action. Remifentanil provides intense analgesia, and has been shown to provide excellent intraoperative haemodynamic stability with rapid postoperative recovery. Remifentanil is a highly effective mu opioid agonist with predictable pharmacokinetics and a close concentration effect relationship (28). Remifentanil for fast-track cardiac anaesthesia provided more safe and stable operating conditions and facilitated earlier tracheal extubation than sufentani1 (29). The results of some workers support the hypothesis that opioid analgesics play an important role in the attenuation Loss of signal power in a transmission.
Attenuation

The reduction in level of a transmitted quantity as a function of a parameter, usually distance. It is applied mainly to acoustic or electromagnetic waves and is expressed as the ratio of power densities.
 of the cytokine response. Crozier crozier

see crosier.
 (30) et al found that IL-6 production was both suppressed and delayed in patients receiving TIVA with propofol and alfentanil after abdominal hysterectomy. The suppression mechanisms are probably related to an interaction with the opioid receptor. Cyclic-AMP (cyclic adenosine monophosphate Cyclic adenosine monophosphate (cAMP, cyclic AMP or 3'-5'-cyclic adenosine monophosphate) is a molecule that is important in many biological processes; it is derived from adenosine triphosphate (ATP). ), as a second messenger, which could stimulate IL-6 secretion is reduced, leading to attenuation of IL-6 and TNF-[alpha] production (31). In this study, using propofol and remifentanil infusion, TNF-[alpha] and IL-6 concentrations were significantly lower in group R than in group F (P <0.05, Table 2).

This study investigated the cytokine levels in patients after open cholecystectomy in order to assess whether there exists a difference in cytokine levels between two different anaesthetic techniques. Serum TNF-[alpha] and IL-6 in both groups had a significantly rapid rise and circulating IL-10 concentrations also had an increase during and after surgery, which was significantly different between the two groups. Propofol and remifentanil seemed to have a significant effect on TNF-[alpha], IL-6 and IL-10 release. Our study certainly suggests that IL-10 concentrations in group R are higher than that in group F patients. Thus, with respect to limitation of surgery-associated stress, TIVA using propofol/remifentanil seems to have a favourable effect. Moreover, induction of the release of anti-inflammatory mediators under TIVA might contribute to the prevention of excessive post-operative inflammation, although this hypothesis would require further testing.

There are several limitations to this study. First, only a small number of patients were studied, limiting its statistical power. Also, we measured only three of several hundred known cytokines. Future studies would benefit from assessments of more cytokines and the effect of other anaesthetic techniques (e.g. regional vs. general). More importantly, we measured cytokine levels but not outcomes. Therefore further clinical studies would be required to ascertain whether the differences in cytokine levels affect any clinical outcome measures.

In summary, our data suggest that anaesthetic technique may have an influence on pro- and anti-inflammatory cytokine levels. TIVA using propofol/remifentanil has a better profile in relation to cytokine levels than a balanced inhalational technique with isoflurane. While the clinical implications of these findings are not known, it is possible that TIVA with propofol and remifentail may offer advantages in terms of inflammatory and immunomodulatory effects compared to an inhalational technique with isoflurane.

ACKNOWLEDGEMENT

We thank Yichang Renfu Corporation (Yichang, China) for their excellent assistance in fund support.

Accepted for publication on September 25, 2007.

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adj.
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A biologically active substance produced by bacteria and consisting of lipopolysaccharide, a complex macromolecule containing a polysaccharide covalently linked to a unique lipid structure, termed lipid A.
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Tending or serving to suppress.

Adj. 1. suppressive - tending to suppress; "the government used suppressive measures to control the protest"
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J.J. KE *, J. ZHAN *, X.B. FENG *, Y. WU *, Y. RAO *, Y.L. WANG [dagger]

Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Hubei Province, Peoples Republic of China

* M.D., Anaesthetist. [dagger] M.D., Professor.

Address for reprints: Professor Yan-Lin Wang, Department of Anesthesiology, Zhongnan Hospital of Wuhan University, East-lake Road 169, Wuhan, Hubei Province, 430071, PR China. wangyanlin0510@yahoo.com
TABLE 1
Characteristics of the two groups (mean [+ or -] SD, n=20)

Characteristics   Group R              Group F

Age (y)           48.0 [+ or -] 12.1   47.6 [+ or -] 13.2
Weight (kg)       52.0 [+ or -] 10.6   52.9 [+ or -] 9.7
Gender (% male)   46                   44
Duration (h)      1.8 [+ or -] 0.3     1.9 [+ or -] 0.3
IV fluid (ml)     1308 [+ or -] 210    1446 [+ or -] 315

TABLE 2
TNF-, IL-6 and IL-10 concentrations in both groups before and after
surgery (mean [+ or -] SD, n=20)

Cytokines             Groups   [T.sub.1]          [P.sub.1] *

TNF-[alpha] (pg/ml)   R        4.2 [+ or -] 0.5   0.1271
                      F        4.5 [+ or -] 0.7

IL-6 (pg/ml)          R        3.4 [+ or -] 0.8   0.1877
                      F        3.1 [+ or -] 0.6

IL-10 (pg/ml)         R        2.7 [+ or -] 0.2   0.1177
                      F        2.5 [+ or -] 0.3

Cytokines             Groups   [T.sub.2]                 [P.sub.2] *

TNF-[alpha] (pg/ml)   R        101 [+ or -] 20 * **      <0.001
                      F        164 [+ or -] 23 **

IL-6 (pg/ml)          R        13.5 [+ or -] 3.4 * **    0.0019
                      F        18.7 [+ or -] 6.1 **

IL-10 (pg/ml)         R        76.2 [+ or -] 15.5 * **   <0.001
                      F        43.2 [+ or -] 11.5 **

Cytokines             Groups   [P.sub.2] **   [T.sub.3]

TNF-[alpha] (pg/ml)   R        <0.001         98 [+ or -] 17 **
                      F        <0.001         132 [+ or -] 19 **

IL-6 (pg/ml)          R        <0.001         13.7 [+ or -] 4.5 **
                      F        <0.001         15.5 [+ or -] 5.2 **

IL-10 (pg/ml)         R        <0.001         63.9 [+ or -] 14.1 * **
                      F        <0.001         38.3 [+ or -] 9.2 **

Cytokines             Groups   [P.sub.3] *   [P.sub.3] **

TNF-[alpha] (pg/ml)   R        0.0607        <0.001
                      F                      <0.001

IL-6 (pg/ml)          R        0.2491        <0.001
                      F                      <0.001

IL-10 (pg/ml)         R        <0.001        <0.001
                      F                      <0.001

P * represents group R compared with group F; P ** represents
comparison with the same group at [T.sub.1].
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Author:Ke, J.J.; Feng, X.B.; Wu, Y.; Rao, Y.; Wang, Y.L.
Publication:Anaesthesia and Intensive Care
Article Type:Clinical report
Geographic Code:9CHIN
Date:Jan 1, 2008
Words:3649
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