The effect of general vs spinal anesthesia on the inflammatory response in orthopedic surgery Jurnalul Român de Anestezie Terapie Intensivã 2012 Vol.19 Nr.1, 13-20 The effect of general vs spinal anesthesia on the inflammatory response in orthopedic surgery T.A. Szabo 1, R.D. Warters 1, B. Kadry 1, R.E. Stroud 2, R.G. Matthews 2, S.M. DeSantis 3, F.G. Spinale 2 1 Department of Anesthesia and Perioperative Medicine, Medical University of South Carolina, Charleston, South Carolina 2 Division of Cardiothoracic Surgery and Anesthesia, Medical University of South Carolina, Charleston, South Carolina 3 Department of Medicine, Medical University of South Carolina, Charleston, South Carolina Abstract Background: Cytokines are regulatory peptides that respond to inflammatory challenges and provide communication between cells during stress. An exaggerated perioperative inflammatory response is associated with poor clinical outcomes. This study tested the hypothesis that a differential profile of cytokine release would occur in patients undergoing orthopedic surgery under general anesthesia vs spinal anesthesia. Methods: Thirty patients undergoing total knee arthroplasty (TKA) were divided in two groups, general anesthesia (GA, n = 15) and spinal anesthesia (SP, n = 15). Blood samples for interleukin-1â (IL-1â), IL-6 and TNFá were drawn at baseline and 6, 12, 24, and 48 hours after incision. The plasma was subjected to enzyme linked multiplex suspension array in order to measure representative cytokines. Results: There was a significant anesthetic effect on each cytokine. resulted in higher IL-6 (p = 0.018), higher TNFá (p < 0.001), and lower IL-1â levels (p = 0.014). There was a twofold higher increase of IL-6 in the SP group compared to the GA group. TNFá levels decreased in the GA group. Conclusions: These findings demonstrate that a differential profile of cytokine release occurs in TKA patients receiving different types of anesthesia. SP elicits a greater inflammatory response than GA as indicated by significantly increased IL-6 and TNFá levels. Since the inflammatory response contributes to overall morbidity, this differential cytokine profile may have significant implications for patients undergoing TKA with pre-existing co-morbidities or increased operative risk. Key words: orthopedic surgery, cytokines, general anesthesia, spinal anesthesia J Rom Anest Terap Int 2012; 19: 13-20 Introduction Cytokines belong to a diverse group of regulatory polypeptides that act locally to respond to inflammatory or ischemic challenges and provide communication between cells during stress [1, 2]. The plasma cytokine response to surgery and trauma involves a complex release of both proinflammatory and antiinflammatory cytokines. Cytokines are characterized by tight gene control, short duration of action and an autocrine or paracrine mode of action, thus Adresa pentru corespondenþã: Tamas A. Szabo, MD, PhD Department of Anesthesiology Room E 212, Ralph H. Johnson Veterans Affairs Medical Center 109 Bee Street Charleston, South Carolina 29401 E-mail: tamas.szabo@va.gov affecting only the immediate environment. The release of cytokines can be stimulated by a number of factors, including ischemia-reperfusion, complement activation, endotoxin-release and the effect of other cytokines. Prototypical inflammatory cytokines include interleukin- 6 (IL-6), IL-1 beta (IL-1â) and tumor necrosis factor alpha (TNFá). There appears to be a significant correlation between the surgical trauma and the IL-6 response suggesting that the overall response is related to the magnitude of tissue damage [3]. Several studies have established that preemptive analgesia (e.g.: epidural blockade, lumbar plexus block with sciatic nerve block) plays an important role in the attenuation of the cytokine response, peripheral and central nervous system sensitization, and pain [4, 5]. Other studies have yielded equivocal results regarding the effect of the anesthetic regimen on the differential release of inflammatory cytokines [6-11].
14 Szabo et al. The primary aim of our study was to compare inflammatory cytokine release in patients undergoing total knee arthroplasties (TKA) under either general anesthesia or spinal anesthesia. We tested the hypothesis that a differential profile of cytokine release would occur in the two different anesthetic groups. As the increased production of pro-inflammatory cytokines might contribute to more severe pain, our secondary aim was to compare analgesic consumption between the two groups. Methods Patients The study obtained approval by the Institutional Review Board of the Ralph H. Johnson VA Medical Center in Charleston, South Carolina. Thirty patients undergoing elective TKA-s gave written informed consent to participate in the study. Patients with a history of rheumatoid arthritis, steroid use within 3 months and non-steroidal anti-inflammatory drug (NSAID) use within one week were excluded. After careful explanation of risks and benefits the patients were given a choice between general and spinal anesthesia. The patients were divided according to the type of anesthetic: fifteen patients were included in the general anesthesia group and another fifteen patients received a spinal anesthetic. Surgical technique was standardized in all 30 patients. After premedication with 2 mg of midazolam, patients were transported to the operating room. Standard monitors (ECG, noninvasive blood pressure, pulse oximetry) were applied. was induced after 3 minutes of preoxygenation. Lidocaine 1 mg/kg, fentanyl 1-2 mcg/ kg, propofol 1-2 mg/kg and vecuronium 0.1 mg/kg were administered. After tracheal intubation, isoflurane 0.8-1.2%, oxygen 50% and air 50% were used to maintain general anesthesia. Patients received 2 g of cefazolin for antibiotic prophylaxis and 0.1 mg/kg of morphine before the surgical incision. In the spinal anesthesia group, a 25 gauge pencil point Whitacreneedle was introduced into the subarachnoid space after sterile preparation and drape in the sitting position. To achieve sensory block (to cold and pinprick) at or above the T10 dermatome, 12.5-15 mg of bupivacaine 0.75% with dextrose 8.25% and 25 mcg of fentanyl were injected after careful aspiration of cerebrospinal fluid. Antibiotic prophylaxis was achieved with cefazolin 2 g prior to surgical incision. Patients were sedated with a low dose propofol drip during the procedure. Blood Sampling Blood samples for IL-1â, IL-6 and TNFá were collected at baseline (after placing a peripheral IV catheter in the holding area), and 6, 12, 24 and 48 hours after the incision. Briefly, 6 mls of blood were collected into a purple top EDTA Vacutainer. Blood samples were then centrifuged at 1200 RPM for 10 minutes. Plasma was decanted and samples were stored in a -70 C freezer. Cytokine Assays Analysis of plasma for IL-1â, IL-6 and TNFá levels was performed using multiplex suspension array technology (Fluorokine MAP Human Cytokine Base Kit LUH000, R&D Systems). Undiluted plasma was incubated for 2 hours at room temperature with analytespecific monoclonal antibodies conjugated to polystyrene beads in a 96-well filter plate. The wells were washed three times and incubated for one hour at room temperature with secondary biotinylated antisera (Invitrogen, Camarillo, California). The wells were washed again before incubation for 30 minutes with streptavidin R-phycoerythin. Finally, the wells were washed and the analyte/bead complexes were resuspended within the filter plate. The identification and quantification of the analyte/bead complexes were determined by flow cytometry with dual excitation lasers (Bio-Plex Suspension Array Workstation; Bio-Rad, Hercules, California). The relative fluorescence obtained for each distinct cytokine was converted to an absolute concentration using standards that were included in each assay. Using this approach, the interassay and intra-assay variation was 10% or less [12]. Data Analysis Data analysis for continuous data for patient demographics and perioperative parameters was performed using 2-tailed Student t-test. Data analysis for categorical data for patient demographics was performed using a chi square test. Repeated measures ANOVAs were conducted on the absolute cytokines values to assess the effect of time post incision, anaesthetic group and the interaction between time and group on each of the cytokines. ANOVA F-tests, degrees of freedom, and p-values are reported. P-values are Bonferonni adjusted. Cytokine levels are reported as mean ± standard error of the mean (SEM). Pairwise comparisons of cytokine levels at each time point versus baseline were also performed using a t-test with adjustment for multiple comparisons. Therefore, pairwise comparisons with p < 0.05 are considered significant. In the analysis of change scores from baseline, a repeated measures ANOVA was performed to assess the effect of time post incision, anesthetic group, and the interaction between time and group on each of the cytokines change scores. ANOVA F-tests, degrees of freedom, and p-values are reported. All statistical procedures were performed with Stata Statistical Software (StataCorp, release 8.0, College Station, Texas).
The effect of general vs spinal anesthesia on the inflammatory response in orthopedic surgery 15 Results Patients in the spinal anesthesia group were older, had a higher incidence of comorbidities, and displayed lower systolic and mean arterial pressures by the end of the surgery (Table 1). None of the patients needed to be admitted to the Intensive Care Unit postopera- tively. Oral and intravenous pain medication consumption was not significantly different in two groups throughout the study period (Table 2). One patient in the spinal group developed respiratory depression 10 hours postoperatively and was treated with naloxone. Baseline IL-1â, IL-6 and TNFá levels were similar in both groups (Table 3). Table 1. Total knee arthroplasty patient demographics and perioperative characteristics General Anesthesia Spinal Anesthesia Age (years) 54.1 ± 2.4 62.9 ± 2.2 Gender (M/F) 14 / 1 15 / 0 BMI (kg/m 2 ) 31.9 ± 1.3 30.2 ± 2.0 Diabetes Mellitus 4 (26%) 5 (33%) Hypertension 8 (53%) 12 (80%) CAD 3 (20%) 4 (26%) COPD 1 (7%) 4 (26%) Case duration (min) 103.1 ± 3.7 94.3 ± 3.3 EBL (ml) 116 ± 28 134 ± 22 LOS (days) 3.8 ± 0.5 3.9 ± 0.3 Baseline Systolic BP (mmhg) 139 ± 4 144 ± 4 Diastolic BP (mmhg) 77 ± 2 78 ± 3 MAP (mmhg) 97 ± 2 100 ± 3 End of Case Systolic BP (mmhg) 139 ± 7 116 ± 4 Diastolic BP (mmhg) 71 ± 4 65 ± 2 MAP (mmhg) 94 ± 5 82 ± 3 BMI: body mass index, BP: blood pressure, CAD: coronary artery disease, COPD: chronic obstructive pulmonary disease, EBL: estimated blood loss, LOS: length of stay, MAP: mean arterial pressure Data are mean ± SEM or numbers (%), p < 0.05 compared to General Anesthesia Table 2. Analgesic consumption of patients after total knee arthroplasty under general anesthesia or spinal anesthesia General Anesthesia Spinal Anesthesia Acetaminophen (mg) DOS 1285 ± 126 886 ± 99 POD#1 1829 ± 191 1404 ± 171 POD#2 1032 ± 155 1010 ± 108 Oxycodone (mg) DOS 16.4 ± 1.6 13.6 ± 1.5 POD#1 23 ± 3.1 20 ± 3.1 POD#2 12 ± 1.5 15 ± 1.9 Morphine (mg) DOS 5.3 ± 0.8 6.2 ± 1.0 POD#1 12.5 ± 2.1 7.3 ± 1.5 POD#2 4.5 ± 0.5 4.3 ± 1.8 DOS: day of surgery, POD: postoperative day Table 3. Baseline cytokine levels of patients General Anesthesia Spinal Anesthesia IL-1â (pg/ml) 0.85 ± 0.14 0.70 ± 0.13 IL-6 (pg/ml) 2.24 ± 0.33 9.21 ± 7.59 TNFá (pg/ml) 2.32 ± 0.40 2.79 ± 0.57 Data are mean ± SEM, p = ns Figures 1-3 show the mean and standard errors of baseline and post-incision cytokine levels by anesthesia group. There was a significant anesthesia effect on each cytokine. Specifically, the use of spinal versus general anesthesia resulted in lower IL-1â (F(df) = 6.22 (1), p = 0.014), higher IL-6 (F(df) = 5.74 (1), p = 0.018), and higher TNFá levels (F(df) = 13.48 (1), p < 0.001). There was also a main effect of time on IL-6
16 Szabo et al. indicating that IL-6 levels increased over time similarly in both groups (F(df) = 4.89 (4), p = 0.001). Pairwise comparisons for each time point revealed that IL-6 levels at 12, 24, and 48 hours were higher versus baseline in the spinal anesthesia group (p < 0.05 for all comparisons). IL-6 levels peaked at 24 hours post-incision in both anesthesia groups (p < 0.05). In general, IL-6 showed an upward trend in both groups over time. TNFα (pg/ml) 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 # p<0.05 vs. Baseline # p<0.05 vs. IL-1 β (pg/ml) 1.2 1.0 0.8 0.6 0.4 0.2 p<0.05 vs. Baseline # p<0.05 vs. 1.0 0.5 0.0 BL 6 hours 12 hours 24 hours 48 hours There was a trend towards increased TNFá-levels in the spinal group, whereas TNFá decreased in patients receiving general anesthesia. 6 hours post incision, TNFá levels were significantly higher in the spinal anesthesia group. Values are Mean ± SEM. Fig. 3. Absolute levels of TNFá over time in the general and spinal anesthesia groups 0.0 BL 6 hours 12 hours 24 hours 48 hours Levels did not change significantly throughout, however there was a trend towards decreased IL-1â levels in the spinal group. Values are Mean ± SEM IL-6 (pg/ml) Fig. 1. Absolute levels of IL-1â over time in the general and spinal anesthesia groups 140 120 100 80 60 40 20 0 p<0.05 vs. Baseline # p<0.05 vs. BL 6 hours 12 hours 24 hours 48 hours IL-6 levels increased significantly from 12 hours postincision in the spinal group and remained increased throughout the entire study period. A significant peak was observed in both groups at 24 hours. Values are Mean ± SEM. Fig. 2. Absolute levels of IL-6 over time in the general and spinal anesthesia groups Figures 4-6 show changes from baseline in the serum concentrations of cytokines in the two anesthesia groups. There was a significant anesthesia effect on IL-6 change score (F(df) = 4.31 (1), p = 0.040). The change score was higher in the spinal anesthesia group. There was also a significant time effect on IL-6 change from baseline (F(df) = 3.31 (3), p = 0.023). Specifically, there was an overall increase in the post incision change score over time. Figure 5 indicates that for IL- 6 and for both groups, all time specific pairwise comparisons of change score with baseline change, were significant (p < 0.05 for all comparisons). Although IL-1β change from baseline (pg/ml) 0.4 0.2 0.0-0.2-0.4 6 hours 12 hours 24 hours 48 hours Values are Mean ± SEM p<0.05 vs. Baseline Fig. 4. Changes in IL-1â concentration over time in the general and spinal anesthesia groups
The effect of general vs spinal anesthesia on the inflammatory response in orthopedic surgery 17 the interaction term did not reach statistical significance, the trend toward an interaction between anesthesia type and time indicated that the increase in change score was more pronounced for the spinal versus the general anesthesia group. There was also a significant effect of general versus spinal anesthesia on TNFá change score (F(df) = 6.12 (1), p = 0.015). The change score was generally positive in the spinal group but negative in the general group. This indicates that in the spinal group, TNFá increased from baseline whereas in the general group, it decreased from baseline (Figure 6). IL-6 change from baseline (pg/ml) 120 100 80 60 40 20 0 p<0.05 vs. Baseline 6 hours 12 hours 24 hours 48 hours There was a significant anesthesia effect on the IL-6 change score (p = 0.040). The time effect was also significant (p = 0.023). Values are Mean ± SEM. Fig. 5. Changes in IL-6 concentration over time in the general and spinal anesthesia groups Discussion TNFα change from baseline (pg/ml) 1.5 1.0 0.5 0.0-0.5-1.0-1.5 p<0.05 vs. Baseline 6 hours 12 hours 24 hours 48 hours There was a significant anesthesia effect on the TNFá change score (p = 0.015). Values are Mean ± SEM. Fig. 6. Changes in TNFá concentration over time in the general and spinal anesthesia groups We assayed 3 cytokines in 30 patients undergoing TKA under general or spinal anesthesia. Our results show that a differential profile of cytokine release occurs with different anesthetic regimens. Namely, spinal anesthesia elicited a greater proinflammatory response than general anesthesia as indicated by significantly higher IL-6 and TNFá levels. Paradoxically, the more pronounced proinflammatory response under spinal anesthesia was not accompanied by increased oral and intravenous analgesic consumption. These findings may have significant implications on the anesthetic choice of patients undergoing TKA with pre-existing co-morbidities. Tissue injury from surgical trauma triggers profound physiological changes including hormonal, metabolic, hematological and immunologic responses. Subsequently, surgery also causes alterations in cytokinerelease. Patients with an exaggerated perioperative inflammatory response may demonstrate increased blood loss, capillary leakage, increased need for respiratory support, disseminated intravascular coagulation, multiple organ failure and cognitive dysfunction [13, 14]. There is conflicting evidence regarding the independent influence of anesthesia on cytokine-production. In patients with rheumatoid arthritis, both proinflammatory and anti-inflammatory cytokine levels decreased significantly 30 minutes after the administration of general anesthesia [15]. Preemptive epidural anesthesia (EDA) was found to yield lower IL-6 levels in patients undergoing laparoscopic hysterectomy [4]. On the other hand, supplemental EDA failed to decrease the changes of proinflammatory cytokines in pancreatoduodenectomy patients and in patients undergoing radical esophagectomy [16, 17]. Proinflammatory and anti-inflammatory cytokine profiles were not significantly different in patients undergoing transurethral resection of the prostate under GA or spinal anesthesia [9]. Similarly, there was no significant difference in serum IL-6 production after laparotomy in mice receiving halothane or combined halothanespinal anesthesia [10]. Moreover, one study could not demonstrate any changes in multiple cytokine-levels pre- vs postoperatively in children undergoing surgery under combined GA/EDA [18]. Accordingly, the goal of our study was to compare inflammatory cytokine release in patients undergoing total knee arthroplasties under either general anesthesia or spinal anesthesia. We hypothesised that a differential profile of cytokine release would occur in the two anesthetic groups.
18 Szabo et al. IL-6 plays an important role in the systemic inflammatory response. High plasma concentrations of IL-6 are believed to reliably reflect the extent and intensity of inflammation [3]. Plasma IL-6 levels increased significantly in patients undergoing total hip replacement on the first two postoperative days regardless of the type of anesthesia [19]. Bjornsson and colleagues [20] found no significant changes in the serum levels of TNFá, IL-1â, IL-10, and IL-12 in patients undergoing total hip replacement under spinal anesthesia, but IL- 6 levels increased significantly from the 3 rd postoperative hour and peaked 6 hours postop. IL-6 levels peaked in the 4 th postoperative hour in patients undergoing total hip replacement under general or combined spinal-epidural anesthesia. However, there were no significant differences between the groups [21]. Significant anesthetic and time effects were observed on IL-6 in our study. Namely, IL-6 levels started to increase significantly from 12 hours in the spinal group and they remained increased throughout the 48-hour study period. A significant peak was observed in both groups at 24 hours postincision. These results indicate that total knee arthroplasty induces a more pronounced proinflammatory response in patients under spinal anesthesia. TNFá has been recognized as a major inflammatory factor that induces the release of IL-6 and IL-1â. Circulatory failure and hypoxia are major stimuli for monocytes to produce and secrete TNFá that is responsible for hypotension, tachycardia, fever and oliguria in septic shock. Naito and coworkers found unchanged TNFá and IL-6-levels in patients undergoing total hip replacement under GA with or without EDA [16]. In the present study however, a significant anesthetic effect was observed on TNFá. resulted in higher TNFá levels, whereas TNFá decreased in patients under general anesthesia. Interestingly, the higher TNFá levels in the spinal anesthesia group were not paralleled by increased IL-1â values. The cholinergic anti-inflammatory pathway may also play an important role in the regulation of inflammation [22]. Inflammatory cytokines (including IL-6 and TNFá) produced at the site of injury activate vagal afferents that reach multiple vagal nuclei in the medulla and hypothalamus. This neural input triggers an immediate anti-inflammatory response inhibiting cytokine expression through efferent vagal activity. It might be possible that general anesthesia modulates this pathway differently than spinal anesthesia. It has been postulated that nociception and proinflammatory cytokines play a mutual up-regulatory role. The increased release of proinflammatory cytokines might lead to more severe pain and vice versa. Etanercept, a TNFá-antagonist, was found to attenuate TNFá, IL-1â and IL-6 expression and preserve the antinociceptive effect of morphine in morphine-tolerant animals [23]. Opioid analgesics may also play an important role in the attenuation of the cytokine response. The stimulation of opioid receptors on the surface of monocytes may lead to decreased camp levels that can decrease IL-6 production. Total intravenous anesthesia (TIVA) with propofol and alfentanil was found to suppress IL-6 production in abdominal hysterectomy patients [24]. In the present study, the patients have received up to 250 mcg of fentanyl and 0.1 mg/kg morphine before surgical incision, therefore the influence of opioid-induced IL- 6 suppression cannot be ruled out. On the other hand, TIVA with propofol, sufentanil and atracurium did not seem to influence cytokine levels in patients undergoing laparoscopic or open cholecystectomies [1]. Interestingly, continuous peripheral nerve blocks and ischemic preconditioning were successful in decreasing postoperative pain scores despite similarly increased proinflammatory cytokine levels in TKA patients [5, 25]. Patients in our GA group did not require less oral or intravenous analgesics despite their attenuated proinflammatory cytokine response. It is important to recognize the limitations of the current study. First, the study was not randomized. Patients were encouraged to choose between general anesthesia and spinal anesthesia after thorough explanation of the potential risks and benefits of each technique. Second, our sample size was relatively small. Third, we did not measure local cytokines. Fourth, postoperative pain control on the surgical floor was managed by the primary service, therefore equianalgesic doses of all intravenous and oral analgesics were used. Finally, only a limited number of cytokines were assayed. In conclusion, our study clearly demonstrates a differential cytokine cascade with different anesthetic regimens. provides sympathectomy, but it does not blunt the inflammatory response. On the contrary, the proinflammatory response induced by total knee arthroplasty is of greater magnitude in patients under spinal anesthesia than under general anesthesia. Paradoxically, the increased release of proinflammatory cytokines is not reflected in increased oral and intravenous analgesic consumption. Acknowledgement The authors thank Ms. Jenna Gillis (Division of Cardiothoracic Surgery and Anesthesia, Medical University of South Carolina, Charleston, South Carolina) for help with the statistical analyses Conflict of interest Nothing to declare
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Perioperative inflammatory response in total knee arthroplasty patients: impact of limb preconditioning. Reg Anesth Pain Med 2010; 35: 412-416 Efectul anesteziei generale vs anestezia spinalã asupra rãspunsului inflamator în chirurgia ortopedicã Rezumat Premize. Citokinele sunt peptide reglatorii care rãspund la agresiunea inflamatorie ºi asigurã comunicarea dintre celule în cursul stresului. Un rãspuns inflamator perioperator exagerat se asociazã cu o evoluþie clinicã nefavorabilã. Studiul de faþã a testat ipoteza existenþei unui profil diferit al eliberãrii de citokine în raport cu tipul anesteziei, generalã vs spinalã, la pacienþii supuºi operaþiilor ortopedice. Metodã. Treizeci de pacienþi supuºi operaþiei de artroplastie totalã de genunchi au fost împãrþiþi în douã grupuri, cu anestezie generalã (GA = 15) ºi cu anestezie spinalã (SP = 15). S-au recoltat probe de sânge pentru mãsurarea interleukinei 1â (IL-1â), IL-6 ºi TNFá, preoperator ºi la 6, 12, 24 ºi 48 de ore dupã incizie. Pentru mãsurarea citokinelor, plasma a fost tratatã dupã o tehnologie de suspensie desfãºuratã multiplex. Rezultate. S-a constatat un efect anestezic semnificativ asupra eliberãrii fiecãreia dintre citokine.
20 Szabo et al. Anestezia spinalã a produs niveluri mai ridicate de IL- 6 (p = 0,018) ºi de TNFá (p < 0,001) ºi mai scãzute de IL-1â (p = 0,014). Creºterea de IL-6 a fost de douã ori mai mare în grupul SP comparativ cu grupul GA. Nivelul de TNFá a scãzut în grupul GA. Concluzii. Datele obþinute demonstreazã un profil diferenþiat al eliberãrii de citokine la pacienþii cu artroplastie totalã de genunchi în funcþie de tipul de anestezie. Anestezia spinalã declanºeazã un rãspuns inflamator mai pronunþat decât anestezia generalã exprimat prin creºterea semnificativã a nivelului de IL- 6 ºi TNFá. Întrucât rãspunsul inflamator contribuie la morbiditatea generalã, acest profil diferenþiat al eliberãrii de citokine poate avea implicaþii semnificative la pacienþii cu artroplastie totalã de genunchi care prezintã co-morbiditãþi sau un risc operator crescut. Cuvinte cheie: chirurgie ortopedicã, citokine, anestezie generalã, anestezie spinalã