**4. The influence of regional anesthesia for stress surgery response**

The choice of anesthesia type as well as technique relates to influence on the immune response and may be important in patients with immunological disorders. This situation occurs in patients with immune system deficiency. Patients suffer from immune system disturbances, due to autoimmune or cancer diseases, appear to require special consideration. Among this group of patients should be expected the pathological reaction of immune system or significant immunosupression caused by the surgery trauma.

The imbalanced immune system can modulate the neuroendocrine system and inflammatory responses to the surgery trauma in terms of production of cytokines, immunoglobins, proliferation of lymphocytes, and phagocytosis monocytes/macrophages. The choice of regional anesthesia techniques allow to avoid the supply of volatile/ intravenous anesthetics agents and the controlled ventilation procedures. Furthermore , the afferent nerves blockade is associated with attenuation of the hormonal response to the surgery stress. The regional anesthesia techniques have a significant effect on the immune

The Stress Response and Its Functional Implications in the Immune

consequences for immune responses.

of cancer (Bar- Yosef et al., 2001; Wada et al., 2007).

al., 1998).

Response After Surgery in Patients with Chronic Inflammation Undergoing Arthroplasty 23

neutrophil activity in patients with the spinal anesthesia compare to general anesthesia. The Th1/T2 (CD4+ T/ CD8+ T) balance is necessary for the immune response - both the humoral and the cell-mediated. The Th1 cells produce the interferon gamma and are responsible for the cell-mediated immunity. The Th2 cells produce interleukin-4 and are more effective in inducing the humoral immunity. Cytokine concentration is altered during the surgery as well as anesthesia, which may effects the Th cell predominance with

The advances in the knowledge on the T helper 1 (Th1) and T helper 2 (Th2) cells revealed that the Th1 cells produce cytokines that stimulate the proliferation of CTLs while Th2 cells produce cytokines that are responsible for the activation of the humoral immune response in healthy people. The use of regional anesthesia allows the weakening of the immunosuppression caused by the operational trauma, which is evidenced by studies demonstrating a greater proportion of the Th1 to Th2 and increased neutrophils activity in patients received spinal anesthesia (Erskine et al., 1992; Erskine et al., 1994; Le-Cras et

It has also been demonstrated the beneficial effect of the spinal anesthesia on the immune system regards with its activity and the relationship with the incidence of cancer metastasis. Compared with the general anesthesia using volatile agents, the spinal anesthesia caused significantly less immunosuppressive effects with less postoperative incidences of metastasis in patients underwent surgery. That confirms the beneficial effects of the regional anesthesia on the immune system and the relationship between its activity and the incidence

**5. The stress response and its functional implications in the immune** 

surgery was evaluated in the patients with the different disease activity.

spinal anesthesia. Hyperbaric bupivacaine in dose 4 mg was used in all cases.

**5.1 Material and methods** 

Patients:

**response after surgery in patients with chronic inflammation (clinical study)**  The connection between the surgery stress and the immune system has been presented in numerous publications and while many aspects of the subject have been discussed, most research has been devoted mainly to patients whose immune system works properly. In the available literature there is little information on the impact of the surgery stress on the immune system in patients with a chronic inflammation which in the light of the accepted hypothesis should contribute to the modulation of the immune system response to the surgery stress. Therefore it can be assumed that the development of the stress surgery response should be altered by abnormalities of immune system associated with chronic inflammation. The previous results had reported by author et al. partially helped to confirm the chronic inflammatory state ability to modify of the response of the immune system to surgery trauma (Lisowska et al., 2008). In view of the fact that many of earlier evaluated patients presented significant advanced chronic inflammatory process that reflected in the high activity disease being evaluated the Disease Activity Score-28 (DAS28) based European League Against Rheumatism (EULAR) response criteria (Fransen & van Riel, 2009). DAS28 seems to be correlated with severity of inflammation; therefore, the immune response to

The 37 patients with long term rheumatoid arthritis scheduled for knee arthroplasty under

system which depends on both the nerve blockade and the administrated local anesthetic drugs (Lisowska, 2008).

The results of study revealed the influence of the bupivacaine presence for the reduction of the synthesis of immunoglobin IgG, IgM, IgA and enhancing the granulocytes phagocytosis. The epidural anesthesia with bupivacaine was associated with lower serum concentration of gammaglobulins (IgG, IgM, IgA) and the complement components C3 and C4 (Gajdosz, 1994).

Bupivacaine is the most popular, long acting local anesthetic with a wide range of administration for peripheral and central nerves blockades. Ropivacaine is also a long acting local anesthetic drug similar to bupivacaine in terms of pharmacological activity, but in contrast to is characterized by the lower cardiotoxity. Lidocaine is the most often and widely used local anesthetic for the peripheral nerves blockades especially in the combination with the bupivacaine for more beneficial balance of duration and onset. Lidocaine is also classified as an anti-arrhythmic agent. Bupivacaine in comparison with the lidocaine shows more potent effect on the function of leukocytes. However, the ropivacaine has been shown its anti-inflammatory properties related to the inhibition of leukocyte function such as the rolling/ adhesion which accompanies the early stage of the local inflammatory response. Moreover, both the ropivacaine and lidocaine could inhibit the CD11b/CD18 up-regulation and the L-selectin down-regulation on neutrophils migration between endothelial cells. There has been found that the effect of the lidocaine was 2.5 times lower than the ropivacaine (Martinsson et al., 1997; Zhang et al., 2000).

The extent of nerves blockade, occurs due to regional anesthesia, appears to have an influence on the neuro-endo-immune response intensity. The endocrine - metabolic stimulation following the surgical procedure can be inhibited by the afferent nerves blockade. The blockade of motor, sensory and afferent sympathetic fibers leads to resulted in predominance of parasympathetic system resulting changes in circulation The intensified circulation may reduce the release of cytokines associated with the tissue ischemia and hypoxia but from the other site a marked low perfusion triggers cytokines burs following hypoxia. The degree of blood flow distribution is directly related to the level of the blockade. It was shown that usage of continuous epidural anesthesia reduced the hormonal stress response and improved the protein metabolism, but it didn't play any significant role in the stimulation of inflammatory response *(*Kehler, 2000*).* Although in comparison with general anesthesia, the epidural anesthesia demonstrate less effect on the activity of natural killer cell (NK), T and B cells (Tonnesen et al., 1988).

The spinal anesthesia is considered as the standard procedure for the orthopedic surgery. The choice of the central blockade is influenced with many benefits such as reduced risk of the postoperative cardiovascular, pulmonary and thromboembolic complications. The prolonged analgesia which spreads onto post operative period is also worth to be emphasized. The patients who underwent surgery with the spinal anesthesia would require greatly less opioids which action is not neutral to the immune system. Further advantages of the regional anesthesia, especially in the RA patients, has ability to avoid the difficult and traumatic intubation. The majority of patients with advanced RA demonstrated the atlanto-axial instability with the great risk of spinal cord compression (Lisowska et al., Jan 2007; 2008).

Many studies have revealed that the regional anesthesia can attenuate the perioperative immunosuppression related to the stress surgery. There are evidences demonstrating a greater number of the Th1 compare to Th2 (CD4+ T and CD8+ T cells) and increased the neutrophil activity in patients with the spinal anesthesia compare to general anesthesia. The Th1/T2 (CD4+ T/ CD8+ T) balance is necessary for the immune response - both the humoral and the cell-mediated. The Th1 cells produce the interferon gamma and are responsible for the cell-mediated immunity. The Th2 cells produce interleukin-4 and are more effective in inducing the humoral immunity. Cytokine concentration is altered during the surgery as well as anesthesia, which may effects the Th cell predominance with consequences for immune responses.

The advances in the knowledge on the T helper 1 (Th1) and T helper 2 (Th2) cells revealed that the Th1 cells produce cytokines that stimulate the proliferation of CTLs while Th2 cells produce cytokines that are responsible for the activation of the humoral immune response in healthy people. The use of regional anesthesia allows the weakening of the immunosuppression caused by the operational trauma, which is evidenced by studies demonstrating a greater proportion of the Th1 to Th2 and increased neutrophils activity in patients received spinal anesthesia (Erskine et al., 1992; Erskine et al., 1994; Le-Cras et al., 1998).

It has also been demonstrated the beneficial effect of the spinal anesthesia on the immune system regards with its activity and the relationship with the incidence of cancer metastasis. Compared with the general anesthesia using volatile agents, the spinal anesthesia caused significantly less immunosuppressive effects with less postoperative incidences of metastasis in patients underwent surgery. That confirms the beneficial effects of the regional anesthesia on the immune system and the relationship between its activity and the incidence of cancer (Bar- Yosef et al., 2001; Wada et al., 2007).
