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BJA Advance Access originally published online on January 11, 2007
British Journal of Anaesthesia 2007 98(2):196-203; doi:10.1093/bja/ael334
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© The Board of Management and Trustees of the British Journal of Anaesthesia 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Effects of epidural anaesthesia on surgical stress-induced immunosuppression during upper abdominal surgery

T. Kawasaki1, M. Ogata1,*, C. Kawasaki1, K. Okamoto2 and T. Sata1

1 Department of Anaesthesiology
2 First Department of Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan

* Corresponding author: Department of Anaesthesiology, University of Occupational and Environmental Health, 1-1-1 Iseigaoka Yahatanishiku, Kitakyushu 807-8555, Japan. E-mail: mogata{at}med.uoeh-u.ac.jp

Accepted for publication October 27, 2006.


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgement
 References
 
BACKGROUND: Previously, we have demonstrated that surgical stress rapidly induced transient hyporesponsiveness of blood cells to endotoxin and that monocyte mCD14 and HLA-DR expression decreased soon after the start of surgery under general anaesthesia. This study was designed to investigate the effects of epidural anaesthesia on surgical stress-induced immunosuppression in patients undergoing upper abdominal surgery.

METHODS: After having obtained informed consent, patients were randomly allocated to receive general anaesthesia (Group G) or general anaesthesia with epidural anaesthesia (Group E). Perioperative changes in neutrophil phagocytic activity, neutrophil respiratory burst activity, monocyte mCD14 and HLA-DR expression, plasma IL-10 concentration, and the LPS-induced TNF-{alpha} production in whole blood were measured.

RESULTS: Surgical stress rapidly depressed neutrophil phagocytic activity, monocyte mCD14 and HLA-DR expression, and LPS-induced TNF-{alpha} production ex vivo (P < 0.05 vs preoperation) in both Group G and Group E. In contrast, the plasma IL-10 concentration increased significantly 2 h after the start of surgery (P < 0.05) in both groups. There were no significant differences between the two groups. The neutrophil respiratory burst activity did not change during the operation in either group.

CONCLUSION: This study showed that the innate immune system is suppressed from the early period of upper abdominal surgery. Subgroup analysis suggested that epidural anaesthesia to T4 dermatome as well as general anaesthesia may not protect patients from this immunosuppression. These results in part explain the impairment of host-defense mechanisms seen in the perioperative period.

Keywords: anaesthesia, general; anaesthetic techniques, epidural; immune response, suppression; surgery, GI


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Acknowledgement
 References
 
Many investigators have reported that surgical stress induces immunosuppression. Major operations are associated with innate immune system dysfunction.12 In addition, surgical stress also affects the initiation of the adaptive response. Recently, we demonstrated that surgical stress rapidly induced transient hyporesponsiveness of whole blood to endotoxin from 2 h after the incision and that plasma IL-10, which increases during surgery, participates in this hyporesponsiveness.3 We also demonstrated that the levels of expression of monocyte mCD14 and HLA-DR, major histocompatibility complex class 2 proteins, that have central roles in antigen presentation to lymphocytes and initiation of the adaptive immune response, were reduced early in surgery under general anaesthesia.4 This impairment increases the risk of developing postoperative complications, such as systemic inflammatory response syndrome, sepsis, and multiple organ failure.5

There are complex interactions between stress hormones and the immune system. Surgical stress evokes increased endogenous secretion of glucocorticoids and catecholamines, which can be measured by the increases in serum cortisol, adrenaline, and noradrenaline levels. The sympathetic nerve block induced by epidural anaesthesia reduces the surgical stress responses of plasma catecholamines and cortisol levels and improves some immune responses, such as natural killer cell cytotoxicity in patients undergoing lower abdominal surgery.6 Nevertheless, some investigators have reported that epidural anaesthesia had no effect on surgical stress in patients undergoing upper abdominal surgery.7 8 The effects of the sympathetic nerve block induced by epidural anaesthesia on surgical stress and the immune response, especially in the early period of surgery, still remain unclear. Therefore, we investigated the effects of the epidural anaesthesia on innate immune function, such as neutrophil function, monocyte surface antigen expression, and ability of TNF-{alpha} production, in patients undergoing upper abdominal surgery.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Acknowledgement
 References
 
After obtaining approval from the Committee on Human Research, we obtained informed consent from 20 ASA I or II patients, who were scheduled for elective partial gastrectomy for gastric cancer, to participate in this study. None of the patients had any infectious diseases or metabolic disturbances, such as diabetes mellitus and adrenal insufficiency, and none were taking any medication.

All of the patients were premedicated with brotizolam (Lendormin®, Nippon Boehringer Ingelheim, Hyogo, Japan), a benzodiazepine, 0.25 mg p.o. 2 h before surgery. The patients were allocated randomly into one of two groups.

Group G (general anaesthesia). General anaesthesia was induced with propofol 2 mg kg–1 and fentanyl 5 µg kg–1 fentanyl, and tracheal intubation was accomplished with vecuronium bromide 0.1 mg kg–1. The anaesthesia was maintained with nitrous oxide 60% and isoflurane (end-tidal concentration 1–3%).

Group E (general anaesthesia with epidural block). An epidural catheter (18 gauge) was placed at a vertebral interspace between T6 and T9, and advanced 3–5 cm in the cephalad direction into the epidural space. After administering mepivacaine, an initial volume of 8–12 ml of 2%, to the epidural space and identifying the level of analgesia (T4–S5) by pinprick perception, general anaesthesia was induced with propofol 2 mg kg–1 and fentanyl 5 µg kg–1. Tracheal intubation was accomplished with vecuronium bromide 0.1 mg kg–1. Anaesthesia was maintained with nitrous oxide 60%, and isoflurane (end-tidal concentration 0.5%), and epidural infusion of mepivacaine 2% at 5–7 ml h–1.

Opioids are well known as immune modulators,9 therefore, we did not use any further opioids in either of the groups. Ventilation of lungs was controlled to maintain an end-tidal carbon dioxide between 4–4.6 kPa. Body temperature was maintained adequately by monitoring the core and skin surface temperatures.

Postoperatively continuous infusion of epidural mepivacaine 1% at 5 ml h–1 along with fentanyl 20 µg h–1 was started in both groups. The patients could use bolus dose of epidural anaesthesia (1% mepivacaine 5 ml) if pain was present. A 10 cm visual analogue pain scale (VAS) was used to assess pain intensity at rest every 8 h after surgery. Supplementary epidural boluses were given when VAS was over 4 cm. Epidural catheter was removed on postoperative day 5.

In the previous studies3 4 and a preliminary study, we confirmed that clinically useful concentrations of inhalation anaesthetics, such as isoflurane and nitrous oxide, had no effect on LPS-induced TNF-{alpha} production, plasma IL-10 concentration, monocyte HLA-DR expression, or monocyte CD14 expression. Blood samples (5 ml) were obtained preoperatively, hours after the skin incision (OPE2H), at the end of surgery (Post.OPE), 24 h after surgery (POD1), and on postoperative day 4 (POD4). To obtain plasma samples, blood was placed in tubes containing heparin (1 U ml–1 final concentration) or EDTA-2Na (1.5 mg ml–1 final concentration) and centrifuged. The supernatant samples were collected and stored at – 80°C until assay.

LPS-induced TNF-{alpha} production in whole blood was measured as reported previously.10 Briefly, blood samples were drawn into heparinized syringes and diluted with five volumes of RPMI 1640 (Nissui Pharmaceutical, Tokyo, Japan). The diluted blood (990 µl) was then placed into a 24-well plate (Becton Dickinson, Lincoln Park, NJ, USA). After incubation at 37°C in 95% air and 5% CO2 for 4 h in the presence of LPS (10 µl) at a final concentration of 10 ng ml–1, the blood was centrifuged at 700g for 10 min to remove blood cells. The supernatant was collected and stored at – 80°C until assay. TNF-{alpha} activity in plasma was determined by colorimetric measurement of L929 cell cytotoxicity. TNF-{alpha} activity was expressed in units per millilitre, which is the reciprocal of the dilution necessary for 50% lysis of the cells.

Plasma IL-10 was measured in duplicate using a commercially available enzyme-linked immunoassay kit (Medgenix, BioSource Europe S.A., Fleurus, Belgium). According to the data sheet supplied by the manufacturer, cross-reactivity with other cytokines in this assay is negligible.

Monocyte HLA-DR expression and mCD14 expression were measured using dual monoclonal antibody staining and flow cytometry. Aliquots of 100 µl of anticoagulated whole blood were mixed with 20 µl of fluorescein isothiocyanate (FITC) coupled RMO52 monoclonal antibody (IMO645, Coulter Immunology, Hialeah, FL, USA) and with 20 µl of phycoerythrin-coupled B8.12.2 monoclonal antibody (IMO464, Coulter Immunology). After incubation in the dark at room temperature for 45 min, lysis medium (Immunolyse, Coulter Immunology) was added to erythrocytes, and the samples were incubated for a further 10 min. The samples were then washed twice and fixed with 0.2% paraformaldehyde. All of the samples were analysed immediately using a flow cytometer and XL software (EPICS-XL, Coulter Electronics, Luton, UK). The monocyte gate was set using the routine position for monocytes in the sideways-scatter and forward-scatter for mononuclear cells. A total of 10 000 monocytes were analysed by flow cytometer. The results are given as the mean fluorescence intensity (MFI).

The amount of intracellular oxygen radical production was determined in freshly drawn heparinized whole blood. A test kit (Bursttest, Orpegen Pharma, Heidelberg, Germany) for determining the oxidative burst of leucocytes in whole blood was used. Single-cell analysis was performed by flow cytometry. Briefly, two aliquots (100 µl) of each sample were incubated (10 min at 37°C) with either phosphate-buffered saline (negative control) or with Escherichia coli that had been opsonized with antibodies and complement from pooled sera. E. coli stimulates the production of reactive oxygen intermediates. After the oxidation step (incubation with substrate for 10 min at 37°C) in which the non-fluorescent substrate, dihydrorhodamine 123, was taken up by phagocytes and converted into the green fluorescent compound rhodamine 123 during the respiratory burst, the whole blood was lysed and fixed. This oxidation is highly specific for the respiratory burst activity. To guarantee that no cell debris, dead cells, or bacteria interfered with the measurement, DNA staining was performed with propidium iodide. All of the samples were analysed immediately using a flow cytometer and XL software (EPICS-XL, Coulter Electronics). The PMN gate was set using the routine position for PMNs in the sideways-scatter and forward-scatter for mononuclear cells. A total of 10 000 PMNs were analysed. The results are given as the MFI.

A test kit (Phagotest, Orpegen Pharma) for determining the phagocytic activity of leucocytes in whole blood was used. Single-cell analysis was performed by flow cytometry. Two aliquots (100 µl) of each sample were incubated with FITC-marked opsonized E. coli, at either 0 (control) or 37°C for 10 min. Cells in the phagocytic system have receptors for a complement component (C3b) and for the constant part of the immunoglobulin molecule (Fc) mediating adhesion of the bacteria to the cell surface and subsequent engulfment. During the incubation period, the FITC-marked E. coli were ingested in the 37°C assay. To exclude extracellular bacteria from the measurement, they were quenched with a staining solution. The subsequent lysis, fixation, DNA-staining, and data acquisition steps were performed in the same manner as in the burst assay. The phagocytosis activity of leucocytes was determined by the amount of FITC-marked E. coli in the phagocytic cells. A total of 10 000 PMNs were analysed. The results are given as the MFI.

The total leucocyte counts and the differential counts were performed using a Celltac {alpha} (Nihon Kohden, Tokyo, Japan). The plasma cortisol concentrations were measured by a radioimmuno assay.

Statistical analysis
All data are presented as mean (SEM). Patient characteristics were compared using unpaired t-test. Differences in all variables between Group G and Group E at individual time points were compared using the two-way repeated measures ANOVA. Bonferroni's correction was applied for multiple comparisons. Differences were considered significant at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Acknowledgement
 References
 
The patient characteristics and operative details are shown in Table 1. There were no significant differences between the two groups in any of these features. Significant leucocytosis and lymphopenia occurred after operation; however, there were no significant differences in leucocyte counts and subpopulations between the two groups at each sampling time points (data not shown). None of the patients received blood transfusions during the perioperative period. All of the patients were discharged from the hospital without any major complications.


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  		Table 1 Patient characteristics in the two groups. Values are mean (SEM). There were no significant differences between the two groups

 
Perioperative changes in neutrophil phagocytic activity are shown in Figure 1A. Neutrophil phagocytic activity decreased significantly 2 h after the beginning of the operation and recovered to the preoperative level by the fourth postoperative day. Subgroup analysis showed that epidural anaesthesia as well as general anaesthesia could not prevent the suppression of phagocytic avtivity (Fig. 1B). At each sampling time points, subgroup data showed no significant differences in neutrophil phagocytic activity between the two groups. Similarly, neutrophil respiratory burst activity showed a tendency to decrease after operation; however, this did not reach statistical significance (Fig. 2A and B).


Figure 3341
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  		Fig 1 Perioperative changes of neutrophil phagocytic activities (MFI). Values are mean (SEM). Pre.OPE, pre-operative (before anaesthesia); OPE2H, 2 h after incision; Post.OPE, the end of operation; POD, postoperative day. G, Group G, general anaesthesia (n = 10). E, Group E, general anaesthesia with epidural anaesthesia (n = 10). *P < 0.05 vs control (Pre.OPE).

 


Figure 3342
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  		Fig 2 Perioperative changes of neutrophil respiratory burst activities (MFI). Values are mean (SEM). G, Group G, general anaesthesia (n = 10); E, Group E, general anaesthesia with epidural anaesthesia (n = 10). *P < 0.05 vs control (Pre.OPE).

 
The perioperative changes in monocyte HLA-DR expression are shown in Figure 3A. Monocyte HLA-DR expression decreased significantly 2 h after the beginning of the operation and did not recover to the preoperative level on the fourth postoperative day. In contrast, the plasma IL-10 concentration increased significantly 2 h after the start of surgery and peaked at the end of the operation (Fig. 4A). The IL-10 concentration recovered to the preoperative level by the fourth postoperative day. At each sampling time point, subgroup data showed no significant differences between Group G and Group E in monocyte HLA-DR expression or plasma IL-10 concentration (Figs 3B and 4B). Subgroup analysis suggested that epidural anaesthesia as well as general anaesthesia did not affect the monocyte HLA-DR expression and plasma IL-10 concentration during upper abdominal surgery.


Figure 3343
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  		Fig 3 Perioperative changes of monocyte HLA-DR expression (MFI). Values are mean (SEM). G, Group G, general anaesthesia (n = 10); E, Group E, general anaesthesia with epidural anaesthesia (n = 10). *P < 0.05 vs control (Pre.OPE).

 


Figure 3344
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  		Fig 4 Perioperative changes of plasma IL-10 concentration. Values are mean (SEM). G, Group G, general anaesthesia (n = 10). E, Group E, general anaesthesia with epidural anaesthesia (n = 10). *P < 0.05 vs control (Pre.OPE).

 
The LPS-induced TNF-{alpha} production in whole blood during the perioperative period is shown in Figure 5A. Consistent with our previous studies,3 4 TNF-{alpha} production decreased significantly 2 h after the start of surgery and reached a minimum at the end of the operation in both groups. LPS-induced TNF-{alpha} production recovered to the preoperative level by the first postoperative day. As mCD14 plays an essential role in transmitting LPS signals intracellularly and ultimately activates TNF-{alpha} production,11 we investigated whether perioperative LPS hyporesponsiveness is related to monocyte mCD14 expression. In a similar way to LPS-induced TNF-{alpha} production, monocyte mCD14 expression decreased significantly 2 h after the start of surgery and recovered to the preoperative level by the first postoperative day (Fig. 6A). Subgroup analysis suggested that epidural anaesthesia as well as general anaesthesia could not prevent the LPS hyporesponsiveness and depressed monocyte mCD14 expression (Figs 5B and 6B). At each sampling time point, subgroup data showed no significant differences between Group G and Group E in LPS-induced TNF-{alpha} production or monocyte mCD14 expression.


Figure 3345
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  		Fig 5 Perioperative changes of LPS-induced TNF-{alpha} production in whole blood ex vivo. Values are mean (SEM). G, Group G, general anaesthesia (n = 10); E, Group E, general anaesthesia with epidural anaesthesia (n = 10). *P < 0.05 vs control (Pre.OPE).

 


Figure 3346
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  		Fig 6 Perioperative changes of monocyte mCD14 expression (MFI). Values are mean (SEM). G, Group G, general anaesthesia (n = 10); E, Group E, general anaesthesia with epidural anaesthesia (n = 10). *P < 0.05 vs control (Pre.OPE).

 
It is well known that the endocrine system affects the immune system. Therefore, we measured plasma cortisol concentration during the perioperative period. Plasma cortisol concentration increased after operation [24.06 (4.9) µg ml–1] and returned to the preoperative level by the first postoperative day [8.55 (3.8) µg ml–1]. At each sampling time point, there were no significant differences in plasma cortisol concentration between the two groups.


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Acknowledgement
 References
 
This study demonstrated that surgical-stress-induced immunosuppression began early during surgery. There were no significant differences between patients receiving general anaesthesia alone and those receiving general anaesthesia with epidural anaesthesia in transitions of the immune system.

Major surgery is associated with neutrophil dysfunction, as indicated by reduced chemotactic ability, phagocytic ability, and superoxide anion production.1 2 Consistent with the results of these studies, our study demonstrated that the phagocytic ability of neutrophils was suppressed rapidly by surgical stress. There were no significant differences between the general anaesthesia group and general anaesthesia with epidural anaesthesia group in the suppression of phagocytic ability. Furthermore, our data suggested that neutrophil respiratory burst activity did not change during the operation. However, some investigators have shown that phagocytic ability and production of reactive oxygen is mediated by circulating neutrophils increased during the postoperative period.12 The reason for these differences remains unclear. It is possible that differences in the methods used for measurement may be involved. The methods used to evaluate neutrophil function after a granulocyte divides may affect the evaluated activated neutrophil function. Our method using whole blood reduces the confounding factors that may be associated with the isolation of neutrophils and it provides a more physiological environment in which to examine neutrophil function.13 The present study suggests that the innate immune system, such as phagocytosis, is suppressed by surgical stress and that epidural anaesthesia was unable to prevent this immunosuppression during upper abdominal surgery.

TNF-{alpha} and IL-1ß induced by LPS play a crucial role in activating phagocytic cells, such as macrophages and neutrophils. Hyporesponsiveness to LPS may contribute at least partially to the high mortality rates in septic disease and trauma.14–17 CD14, a molecule expressed on the surface of macrophage/monocyte and neutrophil cells, is not only the LPS receptor that activates cytokine production, but is also an important receptor that activates the phagocytosis of E. coli.18 In our study, we have shown that epidural anaesthesia failed to prevent LPS hyporesponsiveness and the suppression of monocyte mCD14 expression in patients undergoing partial gastrectomy. Taken together, LPS hyporesponsiveness and the suppression of monocyte mCD14 may explain the innate immune dysfunction via the deactivation of macrophage/monocyte and neutrophil cells during the perioperative period.

It has been reported that epidural anaesthesia has advantageous effects on the immune reaction and stress response to surgical stress. Some investigators have reported that epidural anaesthesia maintains NK cell activity and reduces the stress response in patients undergoing hysterectomy.6 Hole and colleagues19  20 suggested that lymphocyte and monocyte functions were suppressed under general anaesthesia, but maintained under epidural anaesthesia in patients undergoing total hip replacement. Furthermore, they showed that epidural anaesthesia suppressed the increase in serum cortisol concentration during the operation.19 20 Conversely, in patients undergoing upper abdominal surgery, there have been some reports that epidural anaesthesia does not improve immunosuppression or the stress response. Tonnesen and colleagues7 reported that NK cell activity during upper abdominal surgery decreases significantly during general anaesthesia and general-plus-epidural anaesthesia. Norman and Fink8 also showed that epidural anaesthesia did not improve neuroendocrine response in patients undergoing abdominal aortic replacement. Consistent with the results of these studies, we demonstrated here that epidural blockade to T4 dermatome did not prevent immunosuppression and the increase of plasma cortisol concentration during upper abdominal surgery. These findings imply that the advantage effect of epidural anaesthesia on innate immune system is still doubtful, especially in patients undergoing upper abdominal surgery. Loick and colleagues21 reported that high thoracic epidural anaesthesia (anaesthetized dermatomes C6–T10) prevented the increase of plasma epinephrine but not plasma cortisol. Furthermore, Segawa and colleagues22 demonstrated that the epidural blockade up to C8–T2 dermatome suppresses stress response after the skin incision, but not during intra-abdominal procedure of the patients of upper abdominal surgery. The responses of surgical stress after intra-abdominal procedure were suppressed by the epidural blockade up to C3–4 dermatome. These studies indicate that nociceptive neural information is conveyed by the sensory fibres and by the phrenic nerves that innervate the diaphragm during upper abdominal surgery. Therefore, epidural blockade to T4 dermatome may not be sufficient to suppress the stress response during the intraabdominal procedure.

It has been shown that cortisol inhibits TNF-{alpha} production and potentiates IL-10 production.23 24 In previous studies25 26 and in this study, the plasma cortisol concentration increased during upper abdominal surgery, such as in partial gastrectomy or partial hepatectomy. Furthermore, we have shown that epidural blockade fails to suppress the surgical-stress-induced LPS hyporesponsiveness and increase of IL-10 concentration. Previous studies demonstrated that increased serum cortisol impairs PMN functions27 and that increased IL-10 is correlated with a decrease in monocyte HLA-DR expression.28 We assume that the increase of both cortisol and IL-10 are the mechanisms of suppressing immune functions, such as phagocytic activity, LPS hyporesponsiveness, and monocyte HLA-DR expression. Further studies are needed to confirm this assumption.

One possible limitation of this study is that we could not assess the epidural blockade to the T4 dermatome during the operation. We checked the epidural blockade to the T4 dermatome before induction of anaesthesia and postoperatively, however, there was the possibility that the epidural sympathetic blockade was inadequate during the operation and the postoperative period. And the other limitation is that the number of patients selected for this study was small, therefore, the risk of a type 2 error cannot be excluded.

In conclusion, we demonstrated that the innate immune system was suppressed from the early period of upper abdominal surgery. Subgroup analysis suggested that epidural anaesthesia to T4 dermatome in combination with general anaesthesia does not protect patients from this immunosuppression, however, we cannot exclude the possibility that the epidural blockade was inadequate and that of a type 2 error. A higher epidural blockade may change the magnitude of immunosuppression seen in this study. The increase of both cortisol and IL-10 may explain the mechanism behind the suppression of measured immune functions. These results may in part explain the impairment of host-defense mechanisms seen in the perioperative period.


   Acknowledgement
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgement
References
 
This work was supported in part by Grants-in-Aid for Scientific Research 12770850 (T.K.) and 14370499 (M.O.) from the Ministry of Education, Science, Sports, and Culture, Japan.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgement
 References
 
1 Duignan JP, Collins PB, Johnson AH, Bouchier-Hayes D. (1986) The association of impaired neutrophil chemotaxis with postoperative surgical sepsis. Br J Surg 73:238–40.[Web of Science][Medline]

2 Utoh J, Yamamoto T, Utsunomiya T, et al. (1988) Effect of surgery on neutrophil functions, superoxide and leukotriene production. Br J Surg 75:682–5.[Web of Science][Medline]

3 Ogata M, Okamoto K, Kohriyama K, et al. (2000) A role of interleukin 10 on hyporesponsiveness of endotoxin during surgery. Crit Care Med 28:3166–70.[CrossRef][Web of Science][Medline]

4 Kawasaki T, Ogata M, Kawasaki C, et al. (2001) Surgical stress induces endotoxin hyporesponsiveness and an early decrease of monocyte mCD14 and HLA-DR expression during surgery. Anesth Analg 92:1322–6.[Abstract/Free Full Text]

5 Wakefield CH, Carey PD, Foulds S, et al. (1993) Changes in major histocompatibility complex class II expression in monocytes and T cells of patients developing infection after surgery. Br J Surg 80:205–9.[Web of Science][Medline]

6 Tonnensen E and Wahlgreen C. (1988) Influence of extradural and general anaesthesia on natural killer cell activity and lymphocyte subpopulations in patients undergoing hysterectomy. Br J Anaesth 60:500–7.[Abstract/Free Full Text]

7 Tonnesen E, Huttel MS, Christensen NJ, Schmitz O. (1984) Natural killer cell activity in patients undergoing upper abdominal surgery: relationship to the endocrine stress response. Acta Anaesthesiol Scand 28:654–60.[Web of Science][Medline]

8 Norman JG and Fink GW. (1997) The effect of epidural anesthesia on the neuroendocrine response to major surgical stress: a randomized prospective trial. Am Surg 63:75–80.[Web of Science][Medline]

9 McCarthy L, Wetzel M, Sliker JK, Eisenstein TK, Rogers TJ. (2001) Opioids, opioid receptors, and the immune response. Drug Alcohol Depend 62:111–123.[CrossRef][Web of Science][Medline]

10 Ogata M, Matsumoto T, Koga K, et al. (1993) An antagonist of platelet-activating factor suppresses endotoxin-induced tumor necrosis factor and mortality in mice pretreated with carrageenan. Infect Immun 61:699–704.[Abstract/Free Full Text]

11 Ziegler-Heitbrock HW and Ulevitch RJ. (1993) CD14: cell surface receptor differentiation marker. Immunol Today 14:121–5.[CrossRef][Web of Science][Medline]

12 Redmond HP, Watson RW, Houghton T, et al. (1994) Immune function in patients undergoing open vs laparoscopic cholecystectomy. Arch Surg 129:1240–6.[Abstract/Free Full Text]

13 De Rossi L, Gott K, Horn N, et al. (2002) Xenon preserves neutrophil and monocyte function in human whole blood. Can J Anaesth 49:942–5.[Web of Science][Medline]

14 Ertel W, Kremer JP, Kenny J, et al. (1995) Downregulation of proinflammatory cytokine release in whole blood from septic patients. Blood 85:1341–7.[Abstract/Free Full Text]

15 Astiz M, Saha D, Lustbader D, et al. (1996) Monocyte response to bacterial toxins, expression of cell surface receptors, and release of anti-inflammatory cytokines during sepsis. J Lab Clin Med 128:594–600.[CrossRef][Web of Science][Medline]

16 Majetschak M, Flach R, Kreuzfelder E, et al. (1999) The extent of traumatic damage determines a graded depression of the endotoxin responsiveness of peripheral blood mononuclear cells from patients with blunt injuries. Crit Care Med 27:313–8.[CrossRef][Web of Science][Medline]

17 Ziegenfuss T, Wanner GA, Grass C, et al. (1999) Mixed agonistic-antagonistic cytokine response in whole blood from patients undergoing abdominal aortic aneurysm repair. Intensive Care Med 25:279–87.[CrossRef][Web of Science][Medline]

18 Schiff DE, Kline L, Soldau K, et al. (1997) Phagocytosis of gram-negative bacteria by a unique CD14-dependent mechanism. J Leukocyte Biol 62:786–94.[Abstract]

19 Hole A and Unsgaard G. (1983) The effect of epidural and general anaesthesia on lymphocyte functions during and after major orthopaedic surgery. Acta Anaesthesiol Scand 27:135–41.[Web of Science][Medline]

20 Hole A, Unsgaard G, Breivik H. (1982) Monocyte functions are depressed during and after surgery under general anaesthesia but not under epidural anaesthesia. Acta Anaesthesiol Scand 26:301–7.[Web of Science][Medline]

21 Loick HM, Schmidt C, Van Aken H, et al. (1999) High thoracic epidural anesthesia, but not clonidine, attenuates the perioperative stress response via sympatholysis and reduces the release of troponin T in patients undergoing coronary artery bypass grafting. Anesth Analg 88:701–9.[Abstract/Free Full Text]

22 Segawa H, Mori K, Kasai K, et al. (1996) The role of the phrenic nerves in stress response in upper abdominal surgery. Anesth Analg 82:1215–24.[Abstract]

23 van der Poll T, Barber AE, Coyle SM, Lowry SF. (1996) Hypercortisolemia increases plasma interleukin-10 concentrations during human endotoxemia: a clinical research center study. J Clin Endocrinol Metab 81:3604–6.[Abstract]

24 Steer JH, Vuong Q, Joyce DA. (1997) Suppression of human monocyte tumor necrosis factor-alpha release by glucocorticoid therapy: relationship to systemic monocytopenia and cortisol suppression. Br J Clin Pharmacol 43:383–9.[CrossRef][Web of Science][Medline]

25 Ogata M, Yanagida K, Takenaka I, et al. (1988) The effect of anesthesia and partial hepatectomy on plasma rennin and aldosterone: comparison between nitrous oxide-enflurane anesthesia and epidural nitrous oxide anesthesia. Masui 37:163–8.[Medline]

26 Ogata M, Takara H, Shimozawa K, et al. (1986) The mechanism of aldosterone secretion during partial gastrectomy. Masui 35:924–8.[Medline]

27 Dahanukar SA, Thatte UM, Deshmukh UD, et al. (1996) The influence of surgical stress on the psychoneuro-endocrine-immune axis. J Postgrad Med 42:12–4.[Medline]

28 Klava A and Windsor ACJ, et al. (1997) Interleukin-10: A role in the development of postoperative immunosuppression. Arch Surg 132:425–9.[Abstract/Free Full Text]


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S. L. Chavan and M. Ogata
Epidural anaesthesia and stress-induced immunosuppression
Br. J. Anaesth., June 1, 2007; 98(6): 847 - 848.
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Epidural anaesthesia and stress induced immunosuppression
Shivanand L Chavan
British Journal of Anaesthesia, 16 Feb 2007 [Full text]
Epidural anaesthesia and stress induced immunosuppression
Masanori Ogata
British Journal of Anaesthesia, 13 Mar 2007 [Full text]
Epidural analgesia
Peter Faber, et al.
British Journal of Anaesthesia, 13 Mar 2007 [Full text]
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