Thoracic Epidural Anaesthesia Was Not Able to Attenuate Stress-Induced Immunosuppression in Patients Undergoing Major Abdominal Surgery

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1 Med.1 Cairo Univ., Vol. 81, No. 2, June: 65-69, Thoracic Epidural Anaesthesia Was Not Able to Attenuate Stress-Induced Immunosuppression in Patients Undergoing Major Abdominal Surgery MOHAMED A. MAHMOUD, M.D.* and FATEN MAHMOUD, M.D.** The Departments of Anesthesia* and Clinical Pathology**, National Hepatology & Tropical Medicine, Research Institute Abstract Background: Blunting the perioperative stress response and preserving immune function are critical issues for patients undergoing major abdominal surgery. Aim: The present study investigated whether perioperative thoracic epidural block affects postoperative immune response in patients undergoing major abdominal surgery. Patients and Methods: Patients undergoing major abdominal surgery were randomly assigned to either general anesthesia with continuous epidural infusion via epidural catheters that was continued for postoperative analgesia (group E, n=15) or intraoperative general anesthesia and postoperative IV morphine analgesia (group G, n=15). Plasma levels of C- reactive protein (CRP), leukocyte counts, and percentage of total lymphocytes were assessed before and after surgery and on postoperative days (PODs) 1 and 3. Results: There were no significant differences in variables between groups. In both groups, Leukocyte counts were increased on POD1 (each group p<0.05) and POD3 (each group p<0.01). The proportion of lymphocytes decreased from the end of surgery to POD3 (each group p<0.01) and CRP were still increased on POD1 and POD3 (each change, each group p<0.01). Conclusion: Tissue damage and inflammation apparently overcome the effects of thoracic epidural block on stressinduced immunosuppression in patients undergoing major abdominal surgery. Key Words: Thoracic epidural block Stress Induced immunosuppression. Introduction AFFERENT neural blockade by epidural anesthesia can decrease postoperative neuroendocrine stress response. A neuroendocrine response blunted by epidural anesthesia also could affect postoperative immune function because the immune and nervous systems bidirectionally communicate and influence each other [2]. It has been argued Correspondence to: Dr. Mohamed A Mahmoud, The Department of Anesthesia, National Hepatology & Tropical Medicine, Research Institute that nociception and proinflammatory cytokines play a mutual up-regulatory role [3]. Therefore, pain management may influence the immune response in the postoperative period. It has been reported that the alterations in lymphocyte subsets and the increase in white cell counts induced by surgery and general anesthesia can be prevented by epidural analgesia [4-6]. Furthermore, Beilin et al. [7,8] reported that patients treated with patientcontrolled epidural analgesia (PCEA) exhibited attenuated proinflammatory cytokine response in the postoperative period. These reports resulted from procedures below the umbilicus. In upper abdominal or major surgery, however, the effect of epidural anesthesia and analgesia on attenuation of the stress response and preservation of immune function is controversial [9,10]. Major surgery induces a series of inflammatory responses, and the stress response is often exaggerated after major surgery to the detriment of the patient 111,121. Postoperative immune suppression can predispose patients with cancer to the development of postoperative infection [13] or facilitate postoperative tumor growth and metastasis [14,15]. Theoretically, blunting the perioperative stress response and preserving immune function are critical issues for patients undergoing this procedure. Several studies compared postoperative epidural analgesia with postoperative IV analgesia and reported reductions in time spent in the intensive care unit (ICU) and fewer respiratory complications for patients receiving epidural analgesia [17,18]. Aim of the work: The present study was conducted to determine whether thoracic epidural anesthesia and analgesia affect the immune function in patients undergoing major abdominal surgery. 65

2 66 Thoracic Epidural Anaesthesia Was Not Able to Attenuates Patients and Methods The study was performed in National Hepatology & Tropical Medicine, Research Institute in the period between February 2011 and April Institutional and ethics committee approval was obtained for this study, and all participants gave written informed consent. The study group comprised 30 patients (ASA physical status I-II) scheduled for major abdominal surgery. Exclusion criteria: Patients were excluded from the study if they had recently taken corticosteroids or nonsteroidal antiinflammatory medications. The participants were randomly assigned to one of two methods of anesthesia and postoperative pain control. Fifteen patients received general anesthesia with continuous epidural infusion (CEI) through epidural catheters during surgery; CEI was continued for postoperative pain control (group E). Fifteen patients received general anesthesia during surgery with postoperative analgesia accomplished by continuous IV morphine (group G). All patients received midazolam 7.5mg orally lh before surgery. In group E Before induction of anaesthesia, an epidural catheter was inserted between segments Th7/8 and Th11/12 (depending on the surgical procedure) using the midline approach and loss-of-resistance technique. The analgesic area was checked by pinprick after 20min of epidural injection of 8mL 1.5% lidocaine via epidural catheter. Then, CEI of 1% lidocaine with 41.tg/mL fentanyl was administered at 6mL/h during surgery. General anaesthesia was induced by thiopental 3-5mg kg -1 and fentanyl kg -1 Cisatracurium mg kg- 1 or succinylcholine mg kg -1 was given to facilitate orotracheal intubation. Ventilation was controlled mechanically to maintain the partial pressure of expiratory carbon dioxide between 30 and 35mmHg, as measured by capnography. General anesthesia was maintained with oxygen and isoflurane. Intermittent boluses of 501.tg fentanyl were given as necessary. Vecuronium was used to maintain muscular blockade. After the induction of general anesthesia, a double-lumen catheter was inserted via the right internal jugular vein for continuous central venous pressure monitoring and fluid administration. Heart rate (by electrocardiography), CO2 production (by capnography), arterial blood pressure, central venous pressure, blood oxygen saturation (by pulse oximetry), and temperature were monitored. Lactated Ringer's solution was infused at 20mL kg- 1 h-1 during the induction of anesthesia and to maintain preoperative central venous pressure. Hypotension (arterial blood pressure <90mmHg) was corrected by increasing the rate of IV fluid infusion and by administration of ephedrine. Blood was replaced as necessary; the hemoglobin level was maintained at more than 8.0g/dL with transfusion of packed red blood cells, and the albumin level was maintained at more than 3.0g/dL with administration of 5% albumin or fresh-frozen plasma. Temperature was maintained between 36 C and 37 C with the use of a warming device. Arterial blood gases, serum electrolytes (Na+, K+, Cl-, Ca2+), and blood glucose levels were analyzed at least every lh, and these values were maintained within normal ranges by appropriate treatments. After surgery, patients in both groups were transferred to the ICU. CEI of 0.2% ropivacaine with 41.tg/mL fentanyl was administered at 4mL/h via epidural catheter after surgery for postoperative pain control. If a patient complained of pain, an epidural injection of 5mL 0.2% ropivacaine was administrated as a supplemental analgesic. In group G, patients received an initial loading dose of morphine (4-5mg) for pain relief on arrival at the ICU and a continuous infusion of 1mg/h morphine was started. If a patient complained of pain, a 2.5mg IV bolus of morphine was administered as a supplemental analgesic. Pain intensity was assessed at the end of surgery and every 12h after surgery with a box scale (0-10, where 0 is no pain and 10 is the worst pain ever). The independent observer who was not involved in this study assessed pain analgesic area by pinprick and pain intensity. Blood samples (5mL) were collected before and at the end of surgery and on POD1 and POD3. Blood samples were treated with EDTA, and 2mL of blood was used for the analysis of lymphocyte percentage and blood cell counts. The rest of the sample was centrifuged, and the plasma was frozen at 80 C until further analysis. The total leukocyte number and the percentage of total lymphocytes were measured with a cell counter (MAXM-Retic; Coulter) and the plasma levels of C-reactive protein (CRP) were measured before and at the end of surgery and on POD1 and POD3. Statistical analysis: Power calculation had indicated that 15 patients would be required per group to detect a difference of 25% in proportion of lymphocyte, white cell count. Two groups of 15 patients were sufficient to detect both these differences with a power of 80%. Data are expressed as Mean±SD. Student's t-test (unpaired) was used to analyze betweengroup differences in patients characteristics (age, weight, height), duration of surgery, amounts of fluid and blood infused, and amount of blood lost

3 Mohamed A. Mahmoud 67 during surgery. Pain scores and plasma levels of CRP, and the leukocyte count, and the percentage of lymphocyte were analyzed by the Kruskal-Wallis test followed by Dunn's method within and between groups. Differences were considered statistically significant at p<0.05. Results Patient characteristics, duration of surgery (Table 1). Type of Surgery (Table 2). The amounts of fluid and blood infused, and amount of blood lost during surgery were similar between the groups. Pain scores in group G were significantly higher than in group E at the end of surgery (p<0.01), but there was no significant different between groups thereafter (Table 3). The epidural-blocked area at the end of surgery was not assessed exactly because of surgical dressing and slight sedation, but no pain at the cervical, thoracic and abdominal regions was affirmed in all patients of group E. Doses of fentanyl administered in group E and the dose of morphine administered in group G for the first 24 h after surgery were 797±47gg and 35.8±3.4mg, respectively. All variables were similar between groups before surgery. There were no significant differences in any values between the groups. In both groups, the following postoperative values differed significantly in comparison to the preoperative values. The plasma levels of CRP were increased at the end of surgery and on POD1 and POD3 (each group: p<0.01; Table 4C). The leukocyte count was increased on POD 1 (each group p<0.05) and POD3 (each group p<0.01; Table 4A), where as the proportion of lymphocytes decreased from the end of surgery to POD3 (each group p<0.01; Table 4B). Table (1): Demographic data. Age (yr) 57.6±18.6 Weight (kg) 52.5±13.6 Sex (male/female) 11/4 Duration of surgery (h) 4.4±1.4 Values are expressed as Mean±SD. C p<0.05 is considered significant. Table (2): Type of surgery. Group E Group G p (n =15)a (n =15)b value Group E (n =15)a Group G (n =15)b Pancreatectomy. 4 5 Radical gastrectomy 4 4 Colonic resection 6 5 Rectum resection 1 1 Values are expressed as n. 54.9± ±7.3 10/ ± Table (3): Pain scores at rest in each group at each of the time periods examined. Group E (n=15)a Group G (n=15)b Significance End-op 0 (0) 3.7 (1.8) **p<0.01 POD1 0.9 (0.6) 1.3 (0.6) N.S POD2 0.9 (0.8) 1 (0.7) N.S POD3 0.8 (0.5) 0.9 (0.3) N.S Results are mean (SD). Pain score in group G is significantly higher than that in group E at the end of surgery (p<0.01), and this value is significantly higher than those at other time points (p<0.01). Values are mean (SD), n=15. End-Op=End of surgery; POD=Postoperative day. **p<0.01 versus group E. N.S=Not Significant Table (4A,B,C): The postoperative values in comparison to the preoperative values. A Group E Group G Significance Pre-op 7000 (1500) 7300 (2000) End-op 7500 (1800) 7600 (1900) POD (2500) (2000) *p<0.05 POD (2000) (2000) **p<0.01 Leukocytes (/ml) B Group E Group G Significance Pre-op 29 (7) 32 (10) End-op 14 (3.6) 13 (4.3) **p<0.01 POD1 12 (2.3) 13 (2.4) **p<0.01 POD3 14 (2.3) 14 (6.4) **p<0.01 Lymphocytes % C Group E Group G Significance Pre-op 0.9 (0.4) 0.8 (0.3) End-op 4.8 (2.4) 4.6 (3.2) **p<0.01 POD1 8.6 (5.1) 8.8 (4.9) **p<0.01 POD3 10 (4.8) 11 (6.2) **p<0.01 CRP (mg/dl) Table (4) total leukocyte count (A), percentage of lymphocytes (B), and C-reactive protein (CRP) (C). There were no significant differences in any values between the groups. The postoperative values differed significantly in comparison to the preoperative values. Values are mean (SD), n=15. End-Op=End of surgery; POD=Postoperative day. p<0.05 versus preoperative; p<0.01 versus preoperative. Results are mean (SD). a Group E = Continuous epidural infusion.

4 68 Thoracic Epidural Anaesthesia Was Not Able to Attenuates Discussion It is well established that the normal response to stress is immunosuppressive, which is on the first glance protective, but can be harmful in the perioperative setting if prolonged and severe [16]. Our findings indicate that extensive epidural block by epidural catheters was not able to suppress leukocytosis, lymphopenia, increases and CRP after major abdominal surgery. Thus, it appears that tissue damage and inflammation overcome the effects of extensive epidural block on stress responses and immune functions in patients undergoing major abdominal surgery. Postoperative pain was not observed in group E at the end of surgery. Thus, CEI via epidural catheter was able to suppress activation of the sympathetic and somatic nervous systems during surgery. However, CEI did not suppress the stress response despite blockade of the nervous system. It is reportedly difficult to prevent the surgical stress response in procedures above the umbilicus [9,10]. There are a few likely causes of the incomplete effect of epidural anesthesia on the stress response to procedures above the umbilicus [19]. First, the doses of local anesthetic used may not be sufficient to produce complete neural blockade at the surgical site [20]. Second, cytokines directly activate the stress response and are released in larger quantities after surgery above the umbilicus [21]. Segawa et al. [20] reported that a block of the sensory fibers included in the phrenic nerves (C3-5 spinal nerves) is required for a complete block of the endocrine stress response to upper abdominal surgery. Although administration of 1.5% lidocaine provided extensive neural blockade before surgery, we could not confirm the blocked area during continuous infusion of 1% lidocaine with fentanyl. Although the analgesic area was assessed at the end of surgery, it was difficult to check the blocked area exactly by pinprick because of the surgical dressing and incomplete emergence from anesthesia. The doses may not have been adequate to provide complete neural blockade at the surgical site during surgery. However, absence of pain was achieved. Taken together, our findings indicate that the direct effects of cytokines were the likely cause of the surgical stress response after major abdominal surgery. CRP was increased significantly in both groups after surgery; the peak level was observed on POD3. The consistently high level of CRP after surgery indicates that surgical inflammation continues for several days after major abdominal surgery. Volk et al. [5] also reported that PCEA, in comparison with patient-controlled analgesia (PCA), had no influence on indicators of the stress response (CRP and cortisol) after major spine surgery. In our study, leukocytosis and lymphopenia were not prevented by epidural anesthesia and analgesia. Although Volk et al. [5] reported that postoperative epidural anesthesia preserves lymphocytes after major spine surgery, our findings suggest that CEI only affected immune function slightly after major abdominal surgery. The present findings indicate that combined regional/general anesthesia with epidural anesthesia for blockade of afferent neural impulses does not attenuate stress -induced immunosuppression during and after major abdominal surgery. In conclusion, tissue damage and inflammation apparently overcome the effects of thoracic epidural block on stressinduced immunosuppression in patients undergoing major abdominal surgery. We recommend epidural analgesia to improve recovery after major abdominal surgery as a multimodal approach. 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