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Year : 2020  |  Volume : 4  |  Issue : 1  |  Page : 14-17

Differences in the suppression of immune response between general anesthesia and spinal anesthesia in femoral bone surgery

Department of Anesthesiology and Intensive Care, Faculty of Medicine, Udayana University, Denpasar, Bali, Indonesia

Date of Submission26-Nov-2019
Date of Decision30-Dec-2019
Date of Acceptance01-Jan-2020
Date of Web Publication16-Mar-2020

Correspondence Address:
Dr. Tjokorda Gde Agung Senapathi
Department of Anesthesiology and Intensive Care, Faculty of Medicine, Udayana University, Jl. PB Sudirman, Denpasar, Bali 80232
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/BJOA.BJOA_10_19

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Anesthesia is an effective way to control stress response. Surgical injury, different anesthesia techniques, and related drugs can directly or indirectly affect the immune system. The perioperative immunosuppression observed in surgical patients is associated with the neuroendocrine stress exerted through the activation of the autonomic nervous system and the hypothalamic–pituitary–adrenal axis. Dysregulation of this inflammatory process may increase susceptibility to infections and result in postoperative complications, such as wound-healing disturbances and infections leading to sepsis. In this case report which enrolled six patients who underwent femoral bone surgery, three patients were under general anesthesia and three patients were under regional anesthesia. We found that increased neutrophil count and serum C-reactive protein (CRP) concentration were lower in patients under spinal anesthesia compared to those under general anesthesia. In conclusion, the inflammatory response to surgery, which could be seen in the neutrophil count and CRP level, was suppressed during spinal anesthesia to a greater extent than during general anesthesia.

Keywords: C-reactive protein, general anesthesia, neutrophil count, regional anesthesia

How to cite this article:
Agung Senapathi TG, Gede Widnyana I M, Utara Hartawan I G, Ryalino C, Kusuma OI. Differences in the suppression of immune response between general anesthesia and spinal anesthesia in femoral bone surgery. Bali J Anaesthesiol 2020;4:14-7

How to cite this URL:
Agung Senapathi TG, Gede Widnyana I M, Utara Hartawan I G, Ryalino C, Kusuma OI. Differences in the suppression of immune response between general anesthesia and spinal anesthesia in femoral bone surgery. Bali J Anaesthesiol [serial online] 2020 [cited 2020 Aug 3];4:14-7. Available from: http://www.bjoaonline.com/text.asp?2020/4/1/14/280808

  Introduction Top

Surgical injury stimulates the systemic inflammatory response. Different anesthetic techniques for surgery may have an impact on the postoperative systemic inflammatory response and the rate of postoperative infective complications.[1],[2] Anesthetic agents may have both direct and hormone-mediated effects on immune mechanisms, although it may be that the long-term nonspecific hormonal effects of the stress response to anesthesia and surgery may have far more profound implications.[3]

Surgical stress increases the number of T-helper-2 (Th2) cells and decreases the number of T-helper-1 (Th1) cells, resulting in suppressed cell-mediated immunity.[4] C-reactive protein (CRP) is an ancient, highly conserved molecule and a member of the pentraxin family of proteins. CRP is secreted by the liver in response to a variety of inflammatory cytokines. Levels of CRP increase rapidly in response to trauma, inflammation, and infection and decrease just as rapidly with the resolution of the condition. Thus, the measurement of CRP is widely used to monitor various inflammatory states. Patients submitted to anesthesia and surgical procedures suffer diverse immunological alterations, which are difficult to determine if they are induced by anesthetic drugs or by surgical procedural stress.[4],[5]

  Case Report Top

We reviewed six patients aged from 18 to 64 years with American Society of Anesthesiologists physical status I–II (ASA I–II), who had femoral bone surgery with two different anesthetic techniques (general and spinal anesthesia). Laboratory examination found no sign of infection or coagulopathy [Figure 1], [Figure 2], [Figure 3], [Figure 4]. We examined the preoperative complete blood count, CRP, and visual analog scale (VAS). The VAS, which ranges from 0 (no pain) to 100 (very severe pain) was used to measure pain intensity throughout the preoperative period and 24 h after the surgery. The first blood sample was taken before the premedication was given to the patients [Table 1]. The second blood sample was taken 24 h after the surgery [Table 2].
Figure 1: Leukocyte count chart preoperative and 24 h postoperative

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Figure 2: Neutrophil count chart preoperative and 24 h postoperative

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Figure 3: Serum C-reactive protein chart preoperative and 24 h postoperative

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Figure 4: Visual analog scale of pain chart preoperative and 24 h postoperative

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Table 1: Characteristics of the patients who underwent general anesthesia

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Table 2: Characteristics of the patients who underwent spinal anesthesia

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All patients received similar premedication: intravenous midazolam 0.01 mg/kg and standard ASA monitoring were applied to the patients. In general anesthesia, patients were induced with propofol 2 mg/kg, fentanyl 2 μg/kg, and atracurium 0.5 mg/kg. Intraoperative maintenance of general anesthesia was made using air/O2 mixture, sevoflurane, fentanyl, and intermittent atracurium.

Spinal anesthesia is carried out as per our institution's procedure. After skin infiltration with lidocaine, the spinal needle is introduced into the skin, angled slightly cephalad. After the penetration of dura–subarachnoid membranes, which is signaled by the free-flowing cerebrospinal fluid, hyperbaric bupivacaine 0.5% 15 mg is administrated intrathecally. Postoperative analgesia was maintained with fentanyl 0.25 μg/kg/h and paracetamol 500 mg every 6 h. The VAS was measured preoperatively and 24 h after the surgery.[6]

  Discussion Top

The stress response to surgery is affected by several factors, including the type of surgery and anesthesia, the magnitude of surgical injury, duration of operation, and the degree of postoperative pain. Anesthetic technique may modulate the extent of this response. Research has been conducted to find a “stress-free anesthetic technique” to limit neuroendocrine, inflammatory, and immune responses. Attenuation of the endocrine–metabolic response may reduce the frequency of postoperative complications.[7]

General anesthesia and surgical stress are considered to suppress immunity, presumably by directly affecting the immune system or activating the hypothalamic–pituitary–adrenal axis and the sympathetic nervous system. The pathomechanism of the relationship between surgery- and anesthesia technique-induced immunosuppression remains unclear.[8] Transient immunosuppression in patients during anesthesia and surgery may cause postoperative infections. In the immunity against pathogens, the processes of nonspecific defense are of particular importance and engage neutrophils as the significant cell type.[9]

When tissue damage occurs, it may cause an increase in leukocyte counts. The highest counts are seen in patients under general anesthesia. Neutrophil responses consist of bone marrow stimulation under the influence of colony-stimulating factors. There are increased release of polymorphs from the bone marrow reserves into the blood, margination of these cells to the walls of blood vessels, diapedesis through the blood vessel wall into the infected or damaged area, and movement to the invading organism with the help of chemotactic agents and eventually phagocytosis.[1],[10]

Fentanyl is known to enhance natural killer (NK) cells' cytotoxicity and increase NK and cytotoxic (CD8+) cell counts. Some previous studies showed that the administration of fentanyl would attenuate the expression of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-6, and IL-8 in vitro. Patients who underwent femoral bone surgery and received fentanyl-based anesthesia had a higher level of stress hormone and higher levels of pro-inflammatory cytokines compared with patients who received spinal anesthesia.[11]

Cho et al.[12] showed that patients who received propofol–remifentanil anesthesia and postoperative ketorolac analgesia exhibited preserved NK-cell cytotoxicity compared with those who received sevoflurane–remifentanil anesthesia and postoperative fentanyl analgesia. The changes in the total leukocyte, neutrophil, and lymphocyte counts and neutrophil-to-lymphocyte ratio over time were not significant between the groups. Surgical incision, on the other hand, caused a rise in the total leukocyte count, which was maximal in the samples taken in the 24 h postoperatively.[12] Our study showed that the neutrophil count in patients who underwent femoral bone surgery was lower with spinal anesthesia than with general anesthesia.

Spinal anesthesia penetrating the systemic circulation can exert anti-inflammatory and immunosuppressive effects by mechanisms involving ion channel modulation (but not Na + influx) and inhibition of Gq proteins of inflammatory cells, that is, phagocytes. Among other functions, the compounds are also able to inhibit phagocytosis and concomitant respiratory burst with increased production of reactive oxygen species (ROS), serving the oxygen-dependent pathogen degradation and constituting the main functional characteristics of phagocytic cells such as neutrophils and monocytes, crucial for host defense.[13]

One study stated that bupivacaine has its inhibitory effects on the ROS production by phagocytic blood cells, that is, neutrophils, with a concomitant decrease of phagocytosis and the expression impairment of surface receptors involved in this process (FcγRIII [CD16], CR1 [CD35], and CR3 [CD11b/CD18]).[13] ROS inhibition by spinal anesthesia was suggested to be associated with their physicochemical properties, specifically lipid solubility, and to be time dependent. Interestingly, the enantiomer-specific effects of bupivacaine concerning its influence on the ROS production were also noted, with the S-(-) enantiomer displaying significantly less inhibition. On the other hand, S-(-) bupivacaine appeared to be more effective in suppressing neutrophil priming.[14]

In patients under spinal anesthesia, we found that there were lower elevated neutrophil counts compared to patients with general anesthesia. We assumed that it was caused by an increase in the release of neutrophils from the bone marrow by inflammatory cytokines in patients under general anesthesia. Meanwhile, spinal anesthesia suppresses neuroendocrine activity linked to surgical procedures with a sympathetic blockade. As a result, while cortisol levels do not change, cytokine production reduces.

CRP is an acute-phase reactant protein produced in response to inflammation or tissue damage. First, postoperative CRP level is an indicator reflecting the invasiveness of a surgical procedure. Second, the elevated CRP level during the postoperative period is known to be closely associated with the increased leukocyte counts, especially neutrophil count, and some major postoperative complications, including infections. In this case, the reports showed that the increased serum CRP concentration 24 h postoperative was lower in those under spinal anesthesia compared to those under general anesthesia. Some previous studies also confirmed that the anesthetic techniques did influence the acute-phase response based on CRP levels at admission, at delivery, and 24 h after surgery.[15],[16]

The VAS score is widely used to measure pain intensity after surgery. From our case series, we can conclude that there were no significant differences between VAS scores in both techniques.

  Conclusion Top

The inflammatory response to surgery, which could be seen in the neutrophil count and CRP level, was suppressed during spinal anesthesia to a greater extent than during general anesthesia. According to the VAS pain assessment result, spinal anesthesia is superior to general anesthesia when considering patients' satisfaction, side effects, and early postoperative analgesia management.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Smajic J, Tupkovic LR, Husic S, Avdagic SS, Hodzic S, Imamovic S. Systemic Inflammatory Response Syndrome in Surgical Patients. Med Arch 2018;72:116-9.  Back to cited text no. 1
Thwaites CL, Lundeg G, Dondorp AM, Adhikari NKJ, Nakibuuka J, Jawa R, et al. Infection management in patients with sepsis and septic shock in resource-limited setting. In: Dondorp AM, Dünser MW, Schultz MJ, editors. Sepsis Management in Resource Limited Setting. Switzerland: Springer; 2019. p. 163-84.  Back to cited text no. 2
Ionescu DC, Margarit SC, Hadade AN, Mocan TN, Miron NA, Sessler DI. Choice of anesthetic technique on plasma concentrations of interleukins and cell adhesion molecules. Perioper Med (Lond) 2013;2:8.  Back to cited text no. 3
Lederman S, Yellin MJ, Inghirami G, Lee JJ, Knowles DM, Chess L. Molecular interactions mediating T-B lymphocyte collaboration in human lymphoid follicles. Roles of T cell-B-cell-activating molecule (5c8 antigen) and CD40 in contact-dependent help. J Immunol 1992;149:3817-26.  Back to cited text no. 4
Martinez AB. The use of c-reactive protein (CRP) as a marker of the surgical stress in gastrointestinal surgery. Biomed J Sci Tech Res 2018;10:7556-8.  Back to cited text no. 5
Delgado DA, Lambert BS, Boutris N, McCulloch PC, Robbins AB, Moreno MR, et al. Validation of digital visual analog scale pain scoring with a traditional paper-based visual analog scale in adults. J Am Acad Orthop Surg Glob Res Rev 2018;2:e088.  Back to cited text no. 6
Eroǧlu M, Kokulu S, Koca HB, Demirboǧan ME, Baki ED, Özcan Ö. The effects of general and spinal anesthesia on systemic inflammatory response in patients undergoing total knee arthroplasty. Eklem Hastalik Cerrahisi 2016;27:153-9.  Back to cited text no. 7
Kim R. Effects of surgery and anesthetic choice on immunosuppression and cancer recurrence. J Transl Med 2018;16:8.  Back to cited text no. 8
Surhonne N, Hebri C, Kannan S, Duggappa DR, Raghavendra Rao RS, Mapari CG. The effect of anesthetic techniques on neutrophil to lymphocyte ratio in patients undergoing infraumbilical surgeries. Korean J Anesthesiol 2019;72:458-65.  Back to cited text no. 9
Dąbrowska AM, Słotwiński R. The immune response to surgery and infection. Cent Eur J Immunol 2014;39:532-7.  Back to cited text no. 10
Inagi T, Hoshina H, Suzuki M, Wada M, Bito H, Sakamoto A. Remifentanil-induced alterations in neutrophil numbers after surgery. JA Clin Rep 2016;2:5.  Back to cited text no. 11
Cho JS, Lee MH, Kim SI, Park S, Park HS, Oh E, et al. The effects of perioperative anesthesia and analgesia on immune function in patients undergoing breast cancer resection: A prospective randomized study. Int J Med Sci 2017;14:970-6.  Back to cited text no. 12
Meier A, Nizet V. Impact of anesthetics on human neutrophil function. Anesth Analg 2019;128:569-74.  Back to cited text no. 13
Yanagidate F, Strichartz GR. Bupivacaine inhibits activation of neuronal spinal extracellular receptor-activated kinase through selective effects on ionotropic receptors. Anesthesiology 2006;104:805-14.  Back to cited text no. 14
Areda EA, Shafshak WM, Zanaty OM, Hadidi AS, Omar AG. Comparison between effects of two anesthetic techniques on acute stress proteins and d-dimer in patients undergoing lower limb orthopedic surgery. Res Op In Anesth Intens Care 2016;3:14-9.  Back to cited text no. 15
Hashimoto K, Tsuji A, Takenaka S, Ohmura A, Ueki R, Noma H, et al. C-reactive protein level on postoperative day one is associated with chronic postsurgical pain after mastectomy. Anesth Pain Med 2018;8:e79331.  Back to cited text no. 16


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1], [Table 2]


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