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Anesth Analg 2001;92:463-469
© 2001 International Anesthesia Research Society

REGIONAL ANESTHESIA AND PAIN MEDICINE

The Effects of Epidural Block on the Distribution of Lymphocyte Subsets and Natural-Killer Cell Activity in Patients with and without Pain

Masataka Yokoyama, MD, Yoshitaro Itano, PhD, Satoshi Mizobuchi, MD, Hideki Nakatsuka, MD, Ryuji Kaku, MD, Takeaki Takashima, MD, and Masahisa Hirakawa, MD

Department of Anesthesiology & Resuscitology, Okayama University Medical School, 2-5-1, Shikata-cho, Okayama City, Okayama 700-8558, Japan

Address correspondence and reprint requests to Masataka Yokoyama, MD, Department of Anesthesiology and Resuscitology, Okayama University Medical School, 2-5-1, Shikata-cho, Okayama City, Okayama 700-8558, Japan. Address e-mail to masayoko @cc.okayama-u.ac.jp.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Although epidural anesthesia prevents immune suppression during surgery, no reports have elucidated how epidural block affects immune response in nonsurgical patients. We examined changes in proportion of lymphocyte subsets and in natural-killer (NK) cell activity in patients with and without pain. Fifteen patients with pain (Pain group) and 15 preoperative patients without pain (Preoperative group) received three different treatments in random order: epidural block with 7 mL 1% lidocaine, epidural injection of an identical volume of normal saline, and IV injection of 1 mg/kg lidocaine. Blood samples were drawn before and after 30, 60, and 120 min of treatment. During epidural block at 30 and 60 min, both groups showed significantly decreased epinephrine, norepinephrine, and cortisol levels, and the proportion of NK cells decreased, whereas the CD4+/CD8+ ratio increased significantly. NK cell activity in both groups decreased significantly at 30 and 60 min. At 120 min, the variables had all returned to preblock values. During treatments with saline and IV lidocaine, neither group showed significant changes in any of the above variables. We conclude that epidural block causes a transient and significant alteration of lymphocyte subsets and NK cell activity regardless of pain status.

Implications: Epidural block causes a transient and significant alteration of lymphocyte subsets and natural-killer cell activity regardless of pain status. Our results indicate that local sympathetic nerve block may be important in modulating an immune response.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Bidirectional communication clearly exists between the neuroendocrine and immune systems (1). Physical and psychological stress modify immune activity (2–5), for example, by increasing natural-killer (NK) cells and suppressor and cytotoxic T cells, and by decreasing the ratio of helper T to suppressor T cells. Pain represents both physical and mental stress and can modify immune activity. The concept of neuroimmune modulation has become important for patients, in particular those with postoperative, chronic, or cancer pain.

Surgery and the resultant stress response leads to a suppression of immune function (6), and general anesthesia cannot prevent this stress response (7). Epidural anesthesia with local anesthetics suppresses the stress response to procedures below the umbilicus (7,8). Complete suppression of the stress response requires total sympathetic and somatic blockade of the surgical site, which can be provided with extensive epidural anesthesia (9). The relative ineffectiveness of opioids is consistent with the concept that nociceptive pathways are only partially responsible for activation of the stress response (10,11). Thus, pain relief and prevention of the stress response may not be directly coupled. Although the analgesic effects of epidural block on surgical stress have been studied, surgical stress involves numerous factors, including tissue injury and inflammation, anesthetics and other drugs, blood loss and infusion, hemodynamic change, and temperature. There are no reports documenting the change in immune system response after pain relief by epidural block, which can also affect the sympathetic nervous system.

We sought to determine if epidural block for pain relief affects the immune response, particularly changes in the proportion of lymphocyte subsets and NK cell activity in patients with pain. A control study was performed to see if epidural block affects immune system response in patients without pain. We also investigated the effect of time course and IV injection of lidocaine on lymphocyte subsets. To investigate possible pathways involved in the mediation of the immunomodulatory effects, we measured the plasma concentrations of epinephrine, norepinephrine, adrenocorticotropic hormone (ACTH), and cortisol.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Institutional and ethics committee approval were obtained for this study, and all participants gave informed consent. Thirty patients who underwent epidural catheterization in our hospital participated, and a cross-over study was conducted. Fifteen patients (7 men and 8 women; age 59 ± 12 yr; height 161.7 ± 9.3 cm; weight 59.5 ± 10.0 kg) had lower abdominal pain or lower extremity pain because of postherpetic neuralgia and were scheduled to receive continuous epidural block (Pain group). Pain lasted more than 1 mo, and the pain intensity was more than 50 on a visual analog scale (VAS) of 0–100, where 0 is no pain and 100 is the worst pain imaginable. The other 15 patients (8 men and 7 women; age 56 ± 14 yr; height 160.1 ± 8.8 cm; weight 58.6 ± 10.2 kg) who were without pain were scheduled to undergo minor surgery of the lower abdomen or a lower extremity (Preoperative group). Preoperative group diagnoses did not include cancer or other diseases that affect the immune system. None of the participants had an immunological disorder nor received drugs that affect immunological response.

All participants of the Pain group received three different treatments in random order at 1-day intervals: epidural block with 7 mL of 1% lidocaine (Epi-Lido), epidural injection with an identical volume of normal saline (Epi-NS), and IV injection of 1 mg/kg of lidocaine (IV-Lido) to examine whether lidocaine itself affects the immune response. Participants of the Preoperative group received the Epi-Lido and Epi-NS treatments in random order at 1-day intervals. For epidural block, a 19-gauge epidural catheter was inserted into the lumbar epidural space (L2-3 or L3-4) 1 day before the study. The sensory nerve block was assessed by pinprick, and the location of the epidural catheter tip was ascertained by epidurogram. Patients abstained from food, caffeine, and exercise for 4 h and received no epidural infusion for 16 h before participation. The study was performed between 9 and 12 AM.

On the day of the study, participants rested in a supine position on a bed. A 20-gauge IV catheter was inserted into the antecubital fossa of one arm for collection of blood samples and administration of lidocaine, and the catheter was flushed with heparinized normal saline. After catheter insertion, a cuff was placed on the opposite arm and connected to a monitor for automated measurements of heart rate and blood pressure. After 30 min of rest, 15 mL venous blood was drawn, and VAS was obtained. Then, lidocaine or normal saline was administered, and participants continued to rest during 120 min of treatment. At 30, 60, and 120 min of treatment, blood samples were collected, VAS was again checked, and the spread of analgesia was determined by pinprick.

Blood samples were treated with EDTA. Then, 2 mL of blood was used for the analysis of lymphocyte subsets and blood cell count, and 5 mL was used for the analysis of NK cell activity. The rest of the sample was centrifuged, and the plasma was frozen at -80°C until further analysis.

Lymphocyte subsets were analyzed by flow cytometry (EPICS ELITETM; Coulter, Miami, FL) with fluorescent-labeled antibodies specific to the cell markers (Coulter). A 0.1 mL blood sample was incubated for 30 min with monoclonal antibodies at 4°C in the dark. The samples were processed with a Q-prep Immunology StationTM (Coulter), which lyses the erythrocytes in a semiautomatic fashion, stabilizes the leukocytes, and fixes the cells. The percentage of lymphocytes as a function of the total leukocyte count was determined through differential gating after triple-color staining. The following antibodies to lymphocyte antigens were used and cell types were determined: CD3-CD19+ (B cells), CD3+CD19- (T cells), CD3+CD4+ (inducer and helper T cells), CD3+CD8+ (suppressor and cytotoxic T cells), and CD3-CD16+CD56+ (NK cells). This method for lymphocyte subset analysis is accurate and has a high degree of specificity and precision; the coefficient of variation was <2.5% in our measurements. The total leukocyte number and the percentage of total lymphocytes were measured with a cell counter (MAXM-Retic.TM; Coulter).

NK cell activity was measured with a standard 4 h chromium release assay performed in 0.2 mL volumes in microplates (12). Fresh peripheral-blood mononuclear cells were isolated by gradient centrifugation of the blood sample with a LymphoprepTM (Nycomed, Oslo, Norway). Cell viability, assessed with the trypan blue exclusion method, was >98%. Cell populations were titrated for cytolytic activity against 5,000 chromium 51-labeled K562 target cells. Effector-cell suspensions were adjusted to 1 x 106 cells/mL, and an effector-to-target cell ratio of 20:1 was tested. Plates were centrifuged for 2 min at 500 x g before incubation for 4 h at 37°C in 5% CO2 and centrifuged again before collecting equal volumes of supernatant from each well. The radioactivity in the supernatant was determined with a {gamma} counter, and the percentage of 51Cr released was calculated with the following formula: % 51Cr release = (test [cpm] - spontaneous [cpm])/(max [cpm] - spontaneous [cpm]) x 100%, where [cpm] is counts per min. Spontaneous release was determined by incubation of target cells in medium alone, and maximum release was determined by incubation of target cells in 1N HCl. NK cell activity was measured in duplicate. Day-to-day assay variability was evaluated. NK cell activity did not significantly differ by experiment day. In our measurements, the coefficient of variation was <7.5%.

The plasma concentrations of epinephrine and norepinephrine were measured with high-performance liquid chromatography with electrochemical detection according to the method described by Weicker et al. (13). The sensitivity limit of this method was 1 pg/mL for each catecholamine. Commercially available radioimmunoassay kits were used to measure the plasma concentrations of ACTH (Allegro HS-ACTHTM; Nichols Institute, San Juan Capistrano, CA) and cortisol (Amerlex Cortisol RIA KitTM; Amersham, Arlington Heights, IL). The sensitivity limits were 1 pg/mL for ACTH and 0.1 µg/dL for cortisol.

Plasma lidocaine concentrations were measured with an enzyme immunoassay method (EMITTM; Syva, a Syntex Company, Palo Alto, CA) by an automatic analysis system (Aca StarTM; Dade International Inc., Wilmington, DE). This method for lidocaine measurement possesses a high degree of specificity and precision. In our measurements, the coefficient of variation at 0.5, 1.0, 2.5, and 5.0 µg/mL was <10%.

Data are expressed as mean ± SD. Student’s t-test (unpaired) was used for between-group comparisons of age, weight, and number of segments blocked during epidural block. Two-way analysis of variance followed by Duncan’s method was used to compare mean arterial pressure, heart rate, plasma concentrations of epinephrine and norepinephrine, plasma concentrations of ACTH and cortisol, plasma concentration of lidocaine, percentages of lymphocyte subsets, leukocyte number, and NK cell activity between and within groups. VAS was compared by using the Kruskal-Wallis test followed by Dunn’s method. Values were considered statistically significant at P < 0.05.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The two patient groups were similar in age, height, and weight. In the Epi-NS treatment of both groups and IV-Lido treatment, no significant difference occurred in any measured variable during treatment.

At 30 min of Epi-Lido, VAS had decreased in all patients of the pain group (range from 51–85 to 0–18), and 9 of 15 had no pain ( Table 1). At 60 min of Epi-Lido, VAS was still decreased (range 0–35), and at 120 min, it was 45 ± 18. The mean number of segments blocked and plasma lidocaine concentrations during Epi-Lido were similar between the two groups (Table 1). There were no significant differences in mean arterial blood pressure and heart rate between the groups before Epi-Lido (Table 2). During Epi-Lido, mean arterial pressure was decreased significantly in both groups at 30 and 60 min.


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  		Table 1. Changes in VAS, Number of Segments Blocked, and Plasma Lidocaine Concentrations
 

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  		Table 2. Changes in Heart Rate and Mean Arterial Pressure
 
The plasma concentration of norepinephrine in the Pain group was significantly larger than that seen in the Preoperative group before treatments ( Fig. 1). During Epi-Lido, the values of epinephrine, norepinephrine, and cortisol decreased significantly at 30 min in both groups. At 60 min, significant changes were still observed in epinephrine level in the Pain group, norepinephrine level in the Preoperative group, and cortisol level in the Pain group, but these values returned to the pretreatment levels at 120 min in both groups.



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  		Figure 1. Changes in the plasma concentrations of epinephrine, norepinephrine, adrenocorticotropic hormone (ACTH), and cortisol. No measured variables showed significant change during epidural injection with normal saline (Epi-NS) or IV injection with lidocaine (IV-Lido). During epidural block with lidocaine (Epi-Lido), the plasma concentration of epinephrine decreased significantly in the Pain group (from 70 ± 28 pg/mL at 0 min to 43 ± 19 pg/mL at 30 min, P < 0.01, and 48 ± 22 pg/mL at 60 min, P < 0.05) and in the Preoperative group (from 60 ± 33 pg/mL at 0 min to 35 ± 23 pg/mL at 30 min, P < 0.0 5). The plasma concentration of norepinephrine in the Pain group was significantly higher than that in the Preoperative group before the epidural block, and this level decreased significantly in both groups during the block (from 365 ± 88 pg/mL at 0 min to 289 ± 85 pg/mL at 30 min, P < 0.05, in the Pain group, and from 213 ± 86 pg/mL at 0 min to 144 ± 75 pg/mL at 30 min, P < 0.0 5, and 151 ± 75 pg/mL at 60 min, P < 0.05 in the Preoperative group). The plasma concentration of cortisol decreased significantly during the epidural block in both groups (from 13.5 ± 2.9 µg/dL at 0 min to 9.5 ± 2.4 µg/mL at 30 min, P < 0.01, and 10.1 ± 2.6 µg/mL at 60 min, P < 0.01, in the Pain group, and from 10.7 ± 4.9 µg/mL to 7.0 ± 3.2 µg/mL at 30 min, P < 0.05, in the Preoperative group). Mean values ± SD are shown, n = 15. * P < 0.05 vs 0 min, ** P < 0.01 vs 0 min, {dagger} P < 0.05 vs Epi-NS, {dagger}{dagger} P < 0.01 vs Epi-NS, ¶ P < 0.05 vs IV-Lido, ¶¶ P < 0.01 vs IV-Lido.

 
Total leukocyte counts, percentage of lymphocytes within leukocytes ( Table 3), proportion of each lymphocyte subset ( Fig. 2), and NK cell activity ( Fig. 3) were similar between the two groups before treatments. In both groups, total leukocyte counts and percentage of lymphocytes within leukocytes did not change significantly after Epi-Lido (Table 3). In both groups, the proportion of NK cells was decreased significantly at 30 and 60 min of Epi-Lido (Fig. 2). At 30 min, the proportion of CD4+ cells (inducer and helper T cells) was increased and the proportion of CD8+ cells (suppressor and cytotoxic T cells) was decreased, resulting in a significant increase of the CD4+/CD8+ ratio (Fig. 3). A significant decrease was observed in NK cell activity at 30 and 60 min of Epi-Lido (Fig. 3). However, at 120 min of Epi-Lido, all these values showed no significant difference compared to those before Epi-Lido. During Epi-Lido, changes in the distribution of lymphocyte subsets and NK cell activity were similar between groups (Figs. 2,3).


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  		Table 3. Number of Leukocytes and Percentage of Lymphocytes
 


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  		Figure 2. Changes in the distribution of B, T, and natural-killer (NK) cells. During any treatment in both groups, the proportions of B cells and T cells did not change significantly. During epidural block with lidocaine (Epi-Lido) in both groups, significant decreases were observed in the proportion of NK cells (from 15.0 ± 4.6% at 0 min to 8.8 ± 4.1% at 30 min, P < 0.01, and 11.1 ± 5.1% at 60 min, P < 0.05, in the Pain group, and from 14.5 ± 5.0% at 0 min to 8.8 ± 3.7% at 30 min, P < 0.01, and 9.5 ± 3.9% at 60 min, P < 0.01 in the Preoperative group). Mean values ± SD are shown, n = 15. * P < 0.05 vs 0 min, ** P < 0.01 vs 0 min, {dagger} P < 0.05 vs Epi-NS, {dagger}{dagger} P < 0.01 vs Epi-NS, ¶ P < 0.05 vs IV-Lido, ¶¶ P < 0.01 vs IV-Lido.

 


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  		Figure 3. Changes in the CD4+/CD8+ ratio and natural-killer (NK) cell activity. No variables changed significantly during epidural injection with normal saline (Epi-NS) or IV injection with lidocaine (IV-Lido). During epidural block with lidocaine (Epi-Lido), CD4+/CD8+ ratio increased significantly in the Pain group (from 1.75 ± 0.65 at 0 min to 2.44 ± 0.88 at 30 min, P < 0.05) and in the Preoperative group (from 1.76 ± 0.55 at 0 min to 2.33 ± 0.69 at 30 min, P < 0.05). NK cell activity decreased significantly in the Pain group (from 36 ± 11% at 0 min to 26 ± 9% at 30 min, P < 0.05, and 28 ± 10% at 60 min, P < 0.05), and in the Preoperative group (from 30 ± 10% at 0 min to 23 ± 10% at 30 min, P < 0.05, and 24 ± 10% at 60 min, P < 0.05). Mean values ± SD are shown, n = 15. * P < 0.05 vs 0 min, {dagger} P < 0.05 vs Epi-NS, ¶¶ P < 0.01 vs IV-Lido.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
During epidural block, a transient but significant alteration in the distribution of lymphocyte subsets and NK cell activity was observed in both patient groups. The magnitude and direction of these changes were similar between the groups, regardless of patient’s pain status. The plasma concentrations of epinephrine and norepinephrine decreased during epidural block in both groups. These findings indicate that the partial blockade of sympathetic nervous activity by epidural block may play an important role in modifying the distribution of lymphocyte subsets and NK cell activity.

Lymphocyte subsets and NK cell activity show circadian rhythms (14) and are subject to physical and psychological stress (3,4). Therefore, participants were tested at the same time of day and epidural block was performed through an epidural catheter that was inserted beforehand to avoid possible changes from the stimulus of needle puncture. A cross-over study was conducted to investigate the effect of time course by Epi-NS in both groups. Because the IV administration of lidocaine is effective for pain in some patients (15), we conducted a cross-over study to investigate the effect of lidocaine itself by IV-Lido in patients of the Pain group. We regarded the IV injection of lidocaine in patients of the Preoperative group to be inappropriate and unethical. We selected postherpetic neuralgia patients as the Pain group. Reportedly, varicella-zoster virus infection alters the population of CD4+ cells and results in suppression of immunity (16). The patients in the Pain group had over 1-month histories of postherpetic neuralgia, and had been infected with varicella-zoster more than 2 months before this study. Therefore, it is unlikely that lymphocyte function in the Pain group was impaired at the time of the current study.

Pain is a stressful event producing immunological alterations (17). Several studies report the effects of stressful events on lymphocyte subsets and function, and document altered immune response after a variety of physical and psychological stressors (3,4,18,19). Consistent immunologic changes reported during stress include an increase in peripheral NK cells, and suppressor and cytotoxic T (CD8+) cells, and a decrease in the CD4+/CD8+ ratio accompanied by altered NK cell activity. Other studies suggest that changes in the immune system response to various types of stress are related to the degree of physiological and psychological damage (6,20). We hypothesized that epidural block would reduce plasma catecholamine levels more in patients with pain than in those without pain, reflecting the effect of the block on the sympathetic nervous system and reducing the stress caused by pain. Such changes would likely lead to a more significant redistribution of lymphocyte subsets in the Pain group than in the Preoperative group. Contrary to this hypothesis, our results indicate that the magnitude of changes in the distribution of lymphocyte subsets and NK cell activity was virtually equivalent and in the same direction for patients with and without pain. Changes were in the opposite direction to that reported during stress: a decrease in CD8+ and NK cells and an increase in the CD4+/CD8+ ratio.

Although preoperative emotional stress is related to increased secretion of stress-related hormones (21), the preblock levels of norepinephrine in the Pain group were significantly more than those in the Preoperative group. Increased plasma norepinephrine indicates increased sympathetic activity during stress (21). Patients’ stress in the Pain group was potentially more than that in the Preoperative group. However, the distribution of lymphocyte subsets and NK cell activity before the block was similar in the two groups. The pain stress (VAS 63 ± 10, 51–85) in our study might not have been strong enough to alter immune response, or the effect of the epidural block on immune activity might not be dependent on the effect on pain relief.

The mechanism by which epidural block modifies the distribution of lymphocyte subsets and NK cell activity remains unclear. The hypothalamo-pituitary-adrenocortical axis and sympatho-adrenal axis are two important pathways that modify immune response. We measured the plasma concentrations of catecholamines and stress hormones to investigate the possible pathways involved in the mediation of the immunomodulatory effects. Our results show that the concentration of ACTH did not change after the block, although those of catecholamines and cortisol decreased significantly. Lumbar epidural block appears to affect sympathetic signals, including the sympathetic innervation to the adrenal glands, but does not affect pituitary function. Our recent study showed that stellate ganglion block, which does not affect the levels of ACTH and cortisol while decreasing catecholamines, changes the proportion of lymphocyte subsets (22). Our current results indicate that sympathetic activity may play an important role in modulating lymphocyte subsets in response to nerve block.

One mechanism through which the block alters the distribution of lymphocyte subsets may involve interaction between catecholamines and lymphocytes. Infusion of epinephrine elicits the same pattern of immune responses as that seen during mental stress (2), and the increase in peripheral NK cells typically observed under acute stress was inhibited by oral administration of an ß-adrenoceptor antagonist (5). Lymphocytes also have adrenergic receptors and reside in close proximity to sympathetic nerve endings in lymphatic tissue (23). Our current results show that the percentage of change in NK cells was more significant than that of changes in other cell types. Lymphocytes have ß2-adrenergic receptors of varying sensitivities with NK cells having those with the most sensitivity (24). The increased ß2-adrenergic receptor sensitivity expressed in NK cells may help explain their increased mobilization compared with other cell types. Although NK cell activity, as well as the distribution of lymphocyte subsets, might be affected by sympathetic nervous activity, only one effector-to-target cell ratio was tested in this study. Therefore, the observed decrease in NK cell activity could simply have been a result of a smaller proportion of NK cells.

We doubt that changes in heart rate and blood pressure after epidural block cause changes in the distribution of lymphocyte subsets and NK cell activity. Stellate ganglion block, which did not cause any significant change in these variables, modified the distribution of lymphocyte subsets and NK cell activity in our previous study (22).

Lidocaine inhibits NK cell activity in vitro in a dose-dependent manner at the concentrations from 10-5 to 10-3 M (25). However, our results showed that the distribution of lymphocytes and NK cell activity was not altered after IV injection of 1 mg/kg lidocaine. This concentration is much smaller than that used in the above-mentioned in vitro study, and it is unlikely that lidocaine itself affected immune response in the present study.

The present results show that the effects of epidural block on lymphocyte subsets and NK cell activity are transient. However, these results raise the question of whether permanent nerve blocks such as celiac plexus block or sympathetic ganglion block, have an immunologically harmful effect. If permanent nerve blocks caused decreases in NK cells and NK cell activity for a long period, such a change could have a major impact on the condition of patients, in particular those with chronic disease or cancer. We intend to investigate the effect of permanent nerve block on immune activity in the next study.

In conclusion, a transient but significant alteration in the distribution of lymphocyte subsets and NK cell activity by epidural block in patients with and without pain indicates that local sympathetic nerve block may be important in modulating immune response.


   Footnotes
 
Presented, in part, at the annual meeting of the International Anesthesia Research Society, Orlando, Florida, March 7–11, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Accepted for publication September 28, 2000.




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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 2001 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press