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Anesth Analg 2004;98:1086-1092
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000104586.12700.3A

PAIN MEDICINE

Postoperative Epidural Anesthesia Preserves Lymphocyte, but Not Monocyte, Immune Function After Major Spine Surgery

Thomas Volk, MD*, Michael Schenk, MD*, Kristina Voigt, cand. med.*, Stefan Tohtz, MD{dagger}, Michael Putzier, MD{dagger}, and Wolfgang J. Kox, MD, PhD, FRCP*

Departments of *Anesthesiology and Intensive Care and {dagger}Orthopedic Surgery, University Hospital Charité, Campus Mitte, Humboldt-University, Berlin, Germany

Address correspondence to Thomas Volk, MD, Department of Anesthesiology and Intensive Care, University Hospital Charité Campus Mitte, Schumannstr. 20/21, 10117 Berlin, Germany. Address e-mail to thomas.volk{at}charite.de Reprints will not be available from the authors.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Extensive spine surgery is associated with postsurgical pain. Epidural pain therapy may reduce postoperative stress responses and thereby influence immune functions. In a randomized, controlled, double-blinded prospective trial, 54 patients received either conventional patient-controlled IV analgesia (PCIA; morphine 3 mg/15 min) or patient-controlled epidural analgesia (PCEA; 0.125% ropivacaine plus sufentanil 1 µg/mL at a base rate of 12 mL/h and bolus application of 5 mL/15 min). Circulating cytokines, C-reactive protein (CRP), cortisol, and cell-surface receptor expression of immune cells (cluster of differentiation [CD]14, human leukocyte antigen-DR, CD86, CD71, CD3, CD4, CD8, CD16, and CD19) were measured perioperatively to characterize immunological functions. PCEA, compared with PCIA, had no influence on altered levels of circulating cytokines (interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor-{alpha}, monocyte chemoattractant protein-1, and macrophage inhibitory factor) or indicators of the stress response (CRP and cortisol). Also, no significant difference was found in monocyte numbers or their human leukocyte antigen-DR, CD86, or CD71 expression. In contrast, the postoperative decrease in B lymphocytes and T-helper cells was significant in the PCEA group. Natural killer cells decreased significantly in patients receiving PCEA compared with PCIA. Therefore, postoperative epidural pain therapy has no influence on monocyte functions but reduces natural killer cells and preserves B-cell and T-helper cell populations. Epidural analgesia thus influences the specific rather than the innate immune system and potentially blunts the postsurgical lymphocyte depression, which is relevant for infectious resistance.

IMPLICATIONS:Epidural analgesia affects the immune system. Postoperative epidural analgesia, compared with conventional IV opioid therapy, preserves lymphocyte rather than monocyte functions. An improvement of postoperative immune function by epidural analgesia therefore may improve postoperative resistance to infectious complications or to chronic pain states.


   Introduction
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 Abstract
 Introduction
Methods
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Extensive surgery is associated with major systemic inflammatory reactions and pain. The inflammatory reaction to tissue injury may contribute to the observed immunodepression present for at least a week after surgery (1). Postoperative pain is also widely accepted as a contributing factor to immune dysfunctions because of known interactions between the central nervous system and the immune system (2,3). Although it has been studied in animals (4), no evidence is available that shows the influence of postoperative pain on the immune system. The perioperatively activated hypothalamo-pituitary-adrenocortical axis and the sympathoadrenal axis are important modulators of the immune response (5). Afferent neural blockade by epidural anesthesia can decrease the postoperative neuroendocrine stress response (6). Whether a blunted neuroendocrine stress response by epidural anesthesia also affects postoperative immune functions is less well known. Immune functions have traditionally been linked to cell functions of the acquired and innate immune system and circulating inflammatory mediators. Responses to invading microbes include the innate (natural) responses and acquired (adaptive) responses. The innate responses primarily use phagocytic cells (neutrophils, monocytes, and macrophages), complement, acute-phase proteins, and cytokines such as the interferons. Acquired responses involve the proliferation of antigen-specific B and T cells, which occurs when the surface receptors of these cells bind to antigens. Functional alterations of circulating cells can be described by alterations in their surface expression of marker proteins. These phenotypical alterations have been described to be most important on neutrophils, monocytes, and lymphocytes (7).

The aim of our investigation was to define alterations in cellular immune functions when postoperative pain is reduced, by measuring the influence of epidural anesthesia on postoperative immune variables related to monocyte and lymphocyte functions after extensive lumbar spine surgery.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After approval of our local ethics committee (EK 1273) and written, informed consent, 54 patients were randomly assigned to receive either patient-controlled epidural analgesia (PCEA) or IV patient-controlled analgesia (PCIA). Entry criteria included patients older than 18 yr with an absence of preexisting pulmonary diseases (determined by clinical examination, chest radiography, lung function tests, and blood gas analyses), absence of insulin-dependent diabetes mellitus, and clinically relevant renal, hepatic, or cerebrovascular disease. Patients with preoperative signs of infection (such as white blood cell (WBC) count >12000/µL, body temperature >38°C, and C-reactive protein [CRP] >5 mg/dL), patients treated with either cyclooxygenase inhibitors or platelet-inhibitory drugs within the last 7 days before the operation, and patients not able to use a PCIA system were excluded. Patients admitted for emergency surgical intervention were also excluded.

After oral premedication with midazolam 0.1 mg/kg, all patients had standardized general anesthesia. All patients received perioperative antibiotic prophylaxis. Anesthesia was induced with fentanyl 100–150 µg, propofol 2–3 mg/kg, and cisatracurium 0.1–0.15 mg/kg, followed by a continuous infusion of propofol 2–8 mg · kg-1 · h-1 and cisatracurium 0.03 mg · kg-1 · h-1 and fentanyl as required. All patients were ventilated with an oxygen/air mixture (fraction of inspired oxygen, 0.5) to maintain an end-tidal PCO2 of 35–45 mm Hg. A central venous line, a peripheral artery catheter, and a urinary catheter with a tip thermistor were inserted.

Epidural catheters were placed during surgery by the surgeons with the tip approximately 5 cm above the upper edge of the operated area. Approximately 30 min before the end of the operation, all patients received an IV infusion of metamizole (2 g) and 100 µg of fentanyl. After tracheal extubation, patients were neurologically tested to exclude a surgical reintervention. Once patients had no sensory or motor deficit, either epidural or systemic analgesia was started according to a predefined random order by an investigator not involved in immunological measurements or patient care. In both groups, a patient-controlled system was used with a lockout time of 15 min. In the PCEA group, ropivacaine 0.125% plus sufentanil 1.0 µg/mL was used with a background infusion of 12 mL/h and bolus application of 5 mL. In the PCIA group, morphine was used in a concentration of 2.0 mg/mL without background infusion and a bolus size of 3 mg. The epidural catheter was removed on the morning of the fourth postoperative day, and the analgesic therapy was converted to a systemic oral analgesia. Patients received tramadol 100 mg 3 times a day with metamizole 4 g/d for the next 4 days. Pain scores were assessed to compare the analgesic efficacy of the analgesic regimens described previously. The visual analog pain score was used with a scale between 0 ("no pain") and 10 ("unbearable pain"). Pain was measured on the day of surgery and on the first, second, and third day after surgery.

Blood samples were collected before surgery (T0), immediately after the operation (T1), and on the first (T2), third (T3), and seventh (T4) postoperative mornings. Serum and plasma of these samples were immediately stored at -80°C for later analysis. Interleukin (IL)-6, IL-8, IL-10, monocyte chemoattractant protein-1 (MCP-1), macrophage inhibitory factor (MIF), and tumor necrosis factor-{alpha} (TNF-{alpha}) in serum samples were determined by using enzyme-linked immunoassays obtained from DPC Biermann GmbH (Bad Nauheim, Germany) (Milenia® IL-6 sensitivity, 4 pg/mL; Milenia® IL-8 sensitivity, 5 pg/mL; Milenia® IL-10 sensitivity, 3 pg/mL; Milenia® TNF-{alpha} sensitivity, 6 pg/mL) and R&D Systems GmbH (Wiesbaden, Germany) (MCP-1 sensitivity, 5 pg/mL; MIF sensitivity, 32 pg/mL). WBC counts were determined by using a Coulter counter (Cell Dyn; Abbott, Wiesbaden, Germany).

Surface expression of human leukocyte antigen (HLA)-DR, cluster of differentiation (CD)14, CD86, CD71, CD3, CD4, CD8, CD19, and CD16 was measured by using labeled monoclonal antibodies, FACScan®, and Lysys II® software (all from Becton Dickinson, Heidelberg, Germany) as previously described (8). Meanings of these markers are presented in Table 1.


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  		Table 1. Characteristics of Cellular and Circulating Immune Markers Used
 
If not otherwise stated, results are given as mean ± SEM. Differences between the treatment groups with respect to patient characteristics were tested by using Kruskal-Wallis analysis of variance. Differences in markers of immune functions along their time course (cytokines, cell numbers, surface receptors, CRP, and cortisol) were analyzed by repeated-measures analysis of variance on ranks according to Brunner and Langer (9). P < 0.05 was considered statistically significant. We used SPSS® (SPSS Inc., Chicago, IL) and SAS® software (SAS Institute, Cary, NC) for analysis.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Patients entering the study had comparable sex and age. All operative procedures were ventrodorsal reposition spondylodeses of one or two levels (Table 2). Mean pain scores of patients receiving PCIA were 1.9 ± 1.9 (SD) 2 h after surgery, 1.8 ± 1.9 (SD) on the first postoperative day, 1.9 ± 2.2 (SD) on the second postoperative day, and 1.4 ± 1.5 (SD) on the third postoperative day. Mean pain scores of patients receiving PCEA were 0.0 ± 0.1 (SD) 2 h after surgery (significantly less compared with the PCIA group, with P < 0.05), 0.4 ± 1.1 (SD) on the first postoperative day, 0.1 ± 0.4 (SD) on the second postoperative day (significantly less compared with the PCIA group, with P < 0.05), and 0.4 ± 1.3 (SD) on the third postoperative day (significantly less compared with the PCIA group, with P < 0.05).


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  		Table 2. Basic Patient Characteristics
 
Circulating IL-6, IL-8, IL-10, MCP-1, cortisol, and CRP increased with no significant differences between the groups (P values for group comparisons were 0.64, 0.71, 0.42, 0.36, 0.88, and 0.18, respectively). Peak levels were reached earlier for IL-8 (2-fold compared with Time 0; P < 0.05), MCP-1 (3- to 4-fold compared with Time 0; P < 0.05), and IL-10 (5-fold compared with Time 1; P < 0.05) than for IL-6 (65- to 80-fold at Time 2 compared with Time 0; P < 0.05), cortisol (1.5-fold at Time 2 compared with baseline; P < 0.05), and CRP (20- to 30-fold at Time 3 compared with Time 0; P < 0.05). MIF and TNF-{alpha} did not increase perioperatively in either group. IL-8, CRP, MCP-1, and cortisol remained increased at Time 4, whereas IL-10 and IL-6 decreased to preoperative levels (Table 3).


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  		Table 3. Perioperative Circulating Cytokines, Chemokines, and Cortisol
 
Neutrophils and monocytes increased in both groups with peak levels early after the operation (P < 0.01), and no significant differences were observed between groups. In contrast, lymphocyte numbers decreased (significant effect of time in each group, with P < 0.01) and recovered at Time 4, with no significant difference between groups (Table 4). Even though monocyte numbers increased, their surface expression of HLA-DR decreased (significant effect of time in each group, with P < 0.01), and no difference between groups was found (Table 4). The HLA-DR expression remained depressed even at Time 4 in both groups. CD86, a co-stimulatory molecule on monocytes, also decreased (significant effect of time in each group, with P < 0.01) but recovered earlier in patients who received epidural analgesia (Table 4). Activation marker CD71 (transferrin receptor) increased continuously (significant effect of time in each group, with P < 0.01), with no significant differences between groups (Table 4).


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  		Table 4. Perioperative Immune Cell Types and Activation Markers
 
B cells (CD19+ lymphocytes) decreased slightly in the PCIA group, remained unaltered in patients who received epidural analgesia during the first 3 days, and increased in both groups at Time 4. T cells (CD3+ lymphocytes) decreased in both groups (significant effect of time in each group, with P < 0.01) and recovered on the seventh day (Fig. 1).



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  		Figure 1. Perioperative circulating B cells (A) and T cells (B) in patients receiving postoperative epidural analgesia () or IV opioid analgesia (). *Significant effect of group, P < 0.05; **significant effect of group, P < 0.01. PCA = patient-controlled analgesia; MFI = mean fluorescence intensity.

 
Of these, the CD4+ T cells decreased early in patients without epidural analgesia and remained higher in patients treated with epidural analgesia. In both groups, CD4+ T cells were slightly increased after 1 wk compared with baseline, with no difference between groups. CD8+ T cells also increased for 5 days and recovered after a week, with no significant differences between groups. The early decrease in the ratio of CD4+ to CD8+ T cells was abolished in patients who received epidural analgesia (P < 0.02) and had increased by Day 7 (Fig. 2). T cells expressing natural killer (NK) surface markers (CD3/CD16+) decreased in patients with epidural analgesia and remained lower until Time 4 compared with patients who received PCIA (Fig. 2).



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  		Figure 2. Perioperative circulating CD4+ T cells (A), CD8+ T cells (B), and natural killer (NK) cells (C) in patients receiving postoperative epidural analgesia () or IV opioid analgesia (). *Significant effect of time, P < 0.05; **significant effect of group, P < 0.01. PCA = patient-controlled analgesia; MFI = mean fluorescence intensity.

 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
One of the early mediators of an inflammatory reaction is TNF-{alpha}. However, perioperative TNF-{alpha} release has rarely been demonstrated, and the postoperative absence of systemic TNF-{alpha} may indicate that the inflammatory reaction is not due to an infectious or bacterial-activating component.

Because IL-6 is produced at the site of the surgical wound, the concentration of this mediator entering the systemic circulation is correlated with the magnitude of the tissue injury (10). Its influence on the immune system is complex and includes immunosuppression and pain modulation (11). No significant differences between groups were found in this study; this confirms our data from cardiac surgical patients receiving perioperative epidural analgesia (12).

IL-8, a neutrophil chemoattractant and activator, has been reported to be reduced by epidural anesthesia in a small number of patients after chest trauma (13). We were not able to reproduce this effect.

MCP-1 is a strong monocyte/macrophage chemoattractant, and MIF is a potent monocyte/macrophage activator. MCP-1 has been reported to be produced locally in sequestered intervertebral discs (14), and perioperative systemic increases can be abolished by methylprednisolone during cardiac surgery (8). Postoperative MCP-1 release in this study again was much less than in patients undergoing cardiac surgery but was not influenced by epidural analgesia. This indicates that the initiating event of this monocyte chemokine is related to the extent of tissue injury. In contrast to reports of increased systemic release of MIF after coronary surgery (15), we did not observe increases after extensive spinal surgery, which may indicate that the region of the trauma is relevant for systemic MIF levels.

IL-10, which has strong antiinflammatory and immunoinhibitory actions, increased as part of the normal inflammatory response, but no influence of epidural analgesia was found. These findings contradict earlier data in cardiac surgical patients who received preoperative epidural analgesia (12). Because we used postoperative epidural analgesia, the trigger of IL-10 release was not inhibited. However, peak IL-10 levels were roughly eight times higher after coronary artery bypass grafting (CABG) surgery than in this investigation. Even though cortisol levels decrease after epidural analgesia (12,16), no influence on postoperative cortisol levels was found; this indicates that cortisol triggers are activated during the operation and that pain reduction has no influence.

Both monocyte and lymphocyte phenotypes have been suggested to be relevant in postoperative immune depression (7,17). Whereas epidural analgesia induces lymphocyte alterations, very few data on alterations of monocyte levels can be found. In fact, we did not find any difference in monocyte surface expression of HLA-DR, CD86, or CD71 in patients receiving epidural analgesia compared with systemic opioid treatment; this confirms data from CABG patients (12).

Consistent immunological changes after stress include a decrease in the CD4/CD8 ratio and an increase in NK cells and CD8+ T cells (18,19). Epidural anesthesia by lidocaine without an opioid has been reported to increase the CD4/CD8 ratio regardless of whether patients have pain (20). In contrast, systemic opioid treatment decreased the CD4/CD8 ratio in patients who did not have surgery (21). An early decrease in the CD4/CD8 ratio was present in our patients with systemic opioid analgesia, and this was prevented in patients who received epidural analgesia (Fig. 2A). A significantly larger CD4/CD8 ratio was found in patients who received epidural analgesia. Whether this effect is related to epidural analgesia by the ropivacaine used or to fewer systemic effects of opioids remains unclear. Acute pain transiently increases NK cell activity (22). In contrast, NK cells decreased after epidural analgesia in our study. A transient decrease was also observed in patients undergoing short-term anesthesia with lidocaine without surgery (20) and in neonates delivered after epidural anesthesia compared with neonates delivered after general anesthesia (23). Because systemic opioid treatment may increase the number of NK cells (21), we think that epidurally administered local anesthetics may be responsible for this effect. At present, these conclusions do not take into account the different solutions of epidural drugs used and the different lengths of epidural analgesia.

Surgical stress and pain may induce postoperative accelerated lymphocyte apoptosis (24). This accelerated lymphocyte depletion may be associated with the risk of postoperative infectious complications (7,25). A preserved lymphocyte function by epidural analgesia may thus contribute to an improved resistance to postoperative infections.

Taken together, our investigation shows that circulating cytokines related to monocyte activation and monocyte phenotype alterations are not influenced by postoperative epidural pain reduction compared with systemic opioid treatment. However, epidural analgesia influences lymphocyte distribution, increases the postoperative CD4/CD8 ratio and B cells, and decreases NK cells. Therefore, regional analgesia is important in modulating the systemic immune reaction in patients. The attenuated lymphocyte depletion by epidural analgesia may well participate in an improved postoperative host resistance against infections.


   Acknowledgments
 
This work was supported by a research grant from the University Hospital Charité.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication October 15, 2003.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2004 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press