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Serum interleukin-6 response after spinal surgery: estimation of surgical magnitude
J Orthop Sci (2006) 11:241–247 DOI 10.1007/s00776-006-1002-4
Original article Serum interleukin-6 response after spinal surgery: estimation of surgical magnitude Satoru Demura1,2, Keisuke Takahashi2, Norio Kawahara1, Yasuyuki Watanabe2, and Katsuro Tomita1 1 2
Department of Orthopaedic Surgery, Kanazawa University, 13-1 Takaramachi, Kanazawa 920-8641, Japan Department of Orthopedic Surgery, Saitama Medical School, Saitama, Japan
Abstract Background. Serum interleukin-6 (IL-6) has been used for quantitative estimation of the surgical magnitude of major cardiac and thoracoabdominal surgery, but there have been few studies assessing IL-6 as a marker of surgical magnitude of spinal surgery. Methods. We investigated the changes in IL-6 response in comparison to other parameters of surgical magnitude and spinal surgery procedures. The study included 40 patients electively undergoing spinal surgery. The patients were divided into four groups: lumbar laminectomy with posterolateral fusion (PLF), lumbar laminotomy, lumbar open discectomy, and cervical laminoplasty. Serum IL-6, C-reactive protein (CRP), creatine kinase (CK), and the white blood cell (WBC) count were determined in venous blood before surgery, at the end of surgery, and 6 h and the first, third, and seventh days after surgery. Results. Serum IL-6 peaked on the first day and returned to a normal value by the seventh day. The peak IL-6 concentrations on the first day after surgery significantly correlated with CRP, CK, duration of surgery, and estimated blood loss. Regarding lumbar surgeries, the peak IL-6 for laminectomy/ PLF was significantly higher than that for laminotomy/open discectomy or for cervical laminoplasty. Conclusions. Serum IL-6 on the first day varied depending on the surgical procedure used. Therefore, it might be a quantitative marker of surgical magnitude following spinal surgery.
Introduction Attempts to optimize and modify surgical methods are causing an increasing demand for simple, reliable tests that make it possible to evaluate the magnitude of damage resulting from the surgery. The estimation of surgical magnitude has so far been based on the length of the Offprint requests to: S. Demura Received: July 22, 2005 / Accepted: January 12, 2006
skin incision, duration of surgery, and estimated blood loss. These factors, however, do not always indicate the surgical magnitude because of the various local or systemic responses that occur after surgery. Surgical magnitude may be defined as the extent to which the factors that disrupt homeostasis are present. After surgery, immune cells such as macrophages and neutrophils or fibroblasts and endothelial cells are activated locally at the surgical site by the destruction of tissues, and they induce a systemic inflammatory response. The systemic response is controlled by a large number of mediators. The mediators include the proinflammatory cytokines: interleukin-1β (IL-1β), tumor necrosis factor-α (TNFα), and IL-6.1,2 TNFα and IL-1β, which enhance the production of IL-6,3–5 are mainly found at a surgical site and are seldom in peripheral blood,6 whereas IL-6 is more likely to be detected in peripheral blood because it has much longer half-life than IL-1β or TNFα. IL-6, which has many biological activities, such as induction of acute-phase proteins, immunoglobulin synthesis, activation of T cells, induction of ACTH synthesis, and increasing platelets,7 is one of the key mediators of the systemic inflammatory response. Sakamoto et al.8 showed that IL-6 concentration at the surgical site correlated with that in the peripheral blood but was markedly higher than in peripheral blood. It is conceivable that IL-6 in peripheral blood reflects the reaction of both the local and systemic responses. Clinically, the peak IL-6 concentration has been used as a marker of surgical magnitude after major cardiac and thoracoabdominal surgery,9–11 but the kinetics of the IL-6 concentration differs depending on the surgical procedure. There have been few studies assessing the kinetics of IL-6 after spinal surgery.12,13 Therefore, the aim of this study was to investigate the kinetics of IL-6, compare IL-6 to other parameters, and evaluate whether serum IL-6 is a quantitative marker of surgical magnitude after spinal surgery.
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S. Demura et al.: IL-6 response after spinal surgery
Methods
Blood samples
Patients This study included 40 patients undergoing elective spinal surgery. There were 14 women and 26 men, with a median age of 57.5 years (27–77 years). The patients were divided into four groups according to surgical procedure: group I, laminectomy with posterolateral fusion (PLF) for lumbar degenerative spondylolisthesis (10 cases); group II, laminotomy for lumbar spinal stenosis (10 cases); group III, open discectomy for lumber disc herniation (10 cases); group IV, cervical laminoplasty cervical spondylotic myelopathy (9 cases) or cervical ossification of the posterior longitudinal ligament (1 case). No patients suffered from inflammatory conditions (e.g., rheumatoid arthritis) or were being treated with drugs, that are known to affect the acute-phase response. All patients gave informed consent for blood samples to be obtained for this study. Anesthesia and operative procedures All patients were premedicated with 0.5 mg atropine sulfate i.m. 30 min before introduction of anesthesia. General anesthesia was induced with thiopental sodium 5–7 mg/kg and maintained with nitrous oxide, oxygen, and sevoflurane (GOS). Neuromuscular block was achieved with vecuronium bromide. For postoperative analgesia, 15 mg pentazocine and 25–50 mg diclofenac sodium were administered. Laminectomy/PLF was performed at a single level without instrumentation. The resected bone of the spinous process and lamina with hydroxyapatite granules was used for the graft without harvesting iliac bone. Bilateral laminotomy was performed at a single disc level. Discectomy was also performed by small laminotomy at a single level. Unilateral open-door cervical laminoplasty with hydroxyapatite spacers was performed at four levels of the laminae from C3 to C6. We did not use a microscope during these surgeries.
Venous blood samples were obtained before surgery, at the end of surgery, 6 h after the end of surgery, and on the first, third, and seventh days after surgery. For IL-6, C-reactive protein (CRP), and creatine kinase (CK) measurements, samples were collected in heparinized tubes and immediately centrifuged at 3000 rpm for 10 min. They were then stored at −20°C until assayed. To determine the white blood cell (WBC) count, samples were collected in EDTA tubes and analyzed consecutively. Serum IL-6 was measured by enzyme immunoassay. The detection limits of this assay were 0.3 pg/ml for IL-6 and 0.10 mg/dl for CRP. The reference values were 4 pg/ml for IL-6, 0.25 mg/dl for CRP, and 24–195 U/l for CK. Statistical analysis Data on patient age, duration of surgery, and estimated blood loss are expressed as medians with ranges; other data are expressed as medians with 10%, 25%, 75%, and 90% percentiles. For comparison of unpaired values among groups, the Kruskal-Wallis test was used followed by the Scheffe test for multiple comparisons. For comparison of paired values, the Friedman test was used followed by the Wilcoxon test. The Spearman rank correlation test was used to test correlations between variables. P < 0.05 was considered significant. Statistical analysis was performed using the Stat View 5.0 statistical software.
Results The clinical data are summarized in Table 1. There was no significant difference with respect to age. The duration of surgery in group III was significantly shorter than that in the other groups, and that in group I was significantly longer than that in group II (P < 0.05). Estimated blood loss in group I was significantly more
Table 1. Classification of patients and their clinical data Group I II III IV
Surgical procedure
Sex (M/F)
Age (years)
Duration of surgery (min)
Estimated blood loss (ml)
Laminectomy + PLF (n = 10) Laminotomy (n = 10) Open discectomy (n = 10) Laminoplasty (n = 10)
3/7 7/3 8/2 7/3
63.5 (50–72) 64.5 (30–72) 50.0 (27–69) 57.5 (43–77)
181 (159–274)** 146 (110–195)*,** 101 (56–140)* 178 (127–240)
145 (70–240)# 90.0 (50–125)# 40.0 (5–70)## 128 (50–185)##
PLF, posterolateral fusion Values are the median and range *,** Significant differences of duration of surgery in each group (P < 0.05) #,## Significant differences of estimated blood loss in each group (P < 0.05)
S. Demura et al.: IL-6 response after spinal surgery
Fig. 1. Changes in serum interleukin-6 (IL-6) concentrations in 40 patients after spinal surgery. There was statistical significance for the time indicated vs. the preoperative value (*P < 0.05, Friedman and Wilcoxon tests). Data are expressed as the median with 25% and 75% (boxes) and 10% and 90% (error bars) percentiles. Preop, preoperatively; end-op, at the end of surgery
than that in group II or III, and that in group IV was significantly more than that in group III (P < 0.05). The median serum IL-6 concentrations before surgery in all groups were within the normal range (median 1.5 pg/ml, range 0.4–3.8 pg/ml). There was no correlation between the serum IL-6 before surgery and the patient’s age (r = 0.20, P = 0.13), and there was no correlation between the serum IL-6 level on the first postoperative day for each procedure and age (data not shown). In all groups, there was an increase in the serum IL-6 concentration after the end of surgery. The median serum IL-6 peaked on the first day after surgery (29.1 pg/ml, range 7.8–154.0 pg/ml) and decreased rapidly, normalizing by the seventh day (2.9 pg/ml, range 1.0–10.2 pg/ml) (Fig. 1). The median CRP concentrations peaked on the third day after surgery (5.4 mg/dl, range 0.78–18.5 mg/dl), decreased rapidly, but remained elevated on the seventh day (0.77 mg/dl, range 0.24– 4.7 mg/dl) (Fig. 2). The median WBC count peaked on the first day after surgery (9.5 × 10.03/mm3, range 5.8– 14.4 × 103/mm3), decreased moderately, and normalized on the seventh day (5.7 × 10.03/mm3, range 1.8–8.4 × 103/ mm3) (Fig. 3). The median CK level peaked on the first day after surgery (473 U/l, range 127–1931 U/l) and returned to preoperative the value by the seventh day (63 U/l, range 25–341 U/l) (Fig. 4). The median IL-6 concentrations for the four groups (surgical procedures) on the first postoperative day were 85.0 pg/ml (range 18.3–154.0 pg/ml) in group I, 29.1 pg/ml (range 13.0–65.3 pg/ml) in group II, 17.5 pg/
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Fig. 2. Changes in serum C-reactive protein (CRP) concentrations in 40 patients after spinal surgery. There was statistical significance for the times indicated vs. the preoperative value (*P < 0.05, Friedman and Wilcoxon tests). Data are expressed as the median with 25% and 75% (boxes) and 10% and 90% (error bars) percentiles
Fig. 3. Changes in white blood cell (WBC) counts (×103/mm3) in 40 patients after spinal surgery. There was statistical significance for the time indicated vs. the preoperative value (*P < 0.05, Friedman and Wilcoxon tests). Data are expressed as the median with 25% and 75% (boxes) and 10% and 90% (error bars) percentiles
ml (range 7.8–40.8 pg/ml) in group III, and 27.6 pg/ml (range 15.6–50.8 pg/ml) in group IV. The peak serum IL-6 concentration in group I was significantly higher than that in each of the other groups (P < 0.05); thus, these levels varied according to the surgical procedure (Fig. 5). The peak CRP level in group I was higher than
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Fig. 4. Changes in creative kinase (CK) concentrations in 40 patients after spinal surgery. There was statistical significance for the times indicated vs. the preoperative value (*P < 0.05, Friedman and Wilcoxon tests). Data are expressed as the median with 25% and 75% (boxes) and 10% and 90% (error bars) percentiles
Fig. 5. Serum interleukin-6 (IL-6) concentrations on the first day after spinal surgery. Group I, laminectomy with posterolateral fusion (PLF); group II, laminotomy; group III, open discectomy; group IV, cervical laminoplasty. There was statistical significance for group I vs. groups II–IV (*P < 0.05, Kruskal-Wallis and Scheffe tests). Data are expressed as the median with 25% and 75% (boxes) and 10% and 90% (error bars) percentiles
that in group III (P < 0.01) but did not differ from that in groups II and IV (Fig. 6). The peak WBC count did not differ among groups (Fig. 7). The peak CK level was higher in group I than in group III (P = 0.02) but did not differ from those in groups II and IV (Fig. 8).
S. Demura et al.: IL-6 response after spinal surgery
Fig. 6. Serum CRP concentrations on the third day after spinal surgery. There was statistical significance for group I vs. group III (*P < 0.05, Kruskal-Wallis and Scheffe tests). Data are expressed as the median with 25% and 75% (boxes) and 10% and 90% (error bars) percentiles
Fig. 7. WBC count on the first day after spinal surgery. Data are expressed as the median with 25% and 75% (boxes) and 10% and 90% (error bars) percentiles
We examined the correlation between peak serum IL-6 and other parameters. The peak IL-6 concentrations on the first day after surgery correlated well with the duration of surgery (r = 0.46, P = 0.004) and estimated blood loss (r = 0.77, P < 0.001) (Fig. 9A,B). There were significant correlations between the serum IL-6 concentration on the first day and the serum CRP level on the third day (r = 0.55, P = 0.001) (Fig. 9C) and the CK level on the first day (r = 0.50, P = 0.006) (Fig. 9E). The WBC count on the first day after surgery did not
S. Demura et al.: IL-6 response after spinal surgery
Fig. 8. CK concentrations on the first day after spinal surgery. There was statistical significance for group I vs. group III (*P < 0.05, Kruskal-Wallis and Scheffe tests). Data are expressed as the median with 25% and 75% (boxes) and 10% and 90% (error bars) percentiles
correlate with the serum IL-6 concentration on the first day (Fig. 9D). The CRP concentrations on the third day after surgery had good correlation with estimated blood loss (r = 0.50, P = 0.003) but not with the duration of surgery (r = 0.29, P = 0.078). The WBC count did not correlate with the estimated blood loss (r = −0.01, P = 0.95) and the duration of surgery (r = −0.10, P = 0.41).
Discussion The kinetics of the IL-6 concentration differs among surgical procedures. Shenkin et al.9 demonstrated that serum IL-6 concentrations reached a peak 1.5–4.0 h after surgery for elective cholecystectomy. Baigrie et al.11 showed that peak IL-6 concentrations occurred at 4–48 h with elective aortic surgery and then fell sharply from 48 to 72 h. For joint replacement surgery, Kragsbjerg et al.14 showed that peak IL-6 concentrations occurred 6–24 h after surgery. He et al.12 and Takahashi et al.13 showed that the peak IL-6 concentration occurred on the first day after spinal instrumentation surgery. In our series of spinal surgeries, serum IL-6 increased at the end of surgery, reached a peak on the first day, and had normalized by the seventh day. We confirmed that serum IL-6 on the first postoperative day was a quantitative marker for comparing spinal surgeries. It took a longer time to normalize the IL-6 concentration after spinal surgery than after abdominal or cardiac surgery. In most cases of spinal surgery, a part of the bone must be excised or the epidural space
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treated — either being a cause of prolonged postoperative hemorrhage that might require a longer period for the IL-6 to normalize. The CRP level reflects the extent of systemic response and has been used as a marker of surgical magnitude.15,16 Our results showed a significant correlation between the peak serum IL-6 level and the peak serum CRP level and that the peak IL-6 concentrations were seen earlier than the peak CRP concentrations, as shown in previous reports.10,14,17 It has been reported that IL-6 is a mediator of CRP synthesis in the liver.1,2 The results of this study suggest that IL-6 is an early marker of the systemic response after spinal surgery as well. Strecker et al. reported that the CK level reflects the extent of soft tissue damage in trauma patients.18 It is suggested that CK serves to indicate the extent of tissue damage according to the surgery performed. In this study, there was a significant correlation between the serum IL-6 level and the CK level on the first day, which indicates the possibility that IL-6 is reflecting the severity of local tissue damage due to the spinal surgery. It is thought that most postoperative increases in the WBC count correlate with the increases in neutrophil counts. Although neutrophil activation is controlled by various cytokines, glanulocyte colony stimulating factor mainly activates neutrophils from bone marrow to peripheral blood. In this study, IL-6 and the WBC count were the markers showing an earlier response than that indicated by the CRP level. The peak WBC count, however, did not differ among the various types of surgery. Thus, the WBC count may not be sufficiently sensitive to be a marker to show the extent of a postoperative systemic response. Many reports have assessed surgical magnitude based on duration of surgery and estimated blood loss. Shenkin et al.9 and Sakamoto et al.8 reported that serum IL-6 correlated well with the duration of surgery and estimated blood loss. It is true that the peak IL-6 concentrations correlated with these factors for most of our spinal surgery. When we compare surgical magnitude using the same surgical procedure, the duration of surgery and estimated blood loss may serve as quantitative markers. However, when comparing laminectomy/PLF and cervical laminoplasty, the peak IL-6 differed significantly, although the duration of the surgery and the estimated blood loss were almost the same. Therefore, if surgical sites differ, it might be difficult to estimate the surgical magnitude by surgery duration or estimated blood loss alone. Furthermore, it may be impossible to compare the surgical magnitude between microscopic spine surgery (which has a long duration with minimal blood loss) and spine surgery such as excision of a hypervascular tumor (which is associated with excessive bleeding and short surgery duration). IL-6 might be
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S. Demura et al.: IL-6 response after spinal surgery
A
B
C
D
E Fig. 9. A Correlation between peak serum IL-6 concentrations and the duration of surgery. The peak serum IL-6 concentrations significantly correlated with the duration of surgery (Spearman rank correlation test). B Correlation between peak serum IL-6 concentrations and estimated blood loss. The peak serum IL-6 concentrations strongly correlated with estimated blood loss (Spearman rank correlation test). C Correlation between peak serum IL-6 concentrations and peak serum CRP concentrations. The peak serum IL-6 con-
centrations significantly correlated with the peak serum CRP concentrations (Spearman rank correlation test). D Correlation between peak serum IL-6 concentrations and the WBC count on the first day. There was no significant correlation (Spearman rank correlation test). E Correlation between peak serum IL-6 concentrations and peak CK concentrations. The peak serum IL-6 concentrations significantly correlated with the peak CK concentrations (Spearman rank correlation test)
S. Demura et al.: IL-6 response after spinal surgery
reflecting surgical magnitude independent of the estimated blood loss or duration of surgery. These results indicate that the serum IL-6 level reflects both the local and systemic responses, that is, the surgical magnitude during spinal surgery. Peak IL-6 has been used as an index of surgical magnitude for cardiovascular and thoracoabdominal surgery. Cruickshank et al.10 and Kragsbjerg et al.14 showed that the peak IL-6 level differed among surgical procedures and was a sensitive marker of surgical magnitude. We compared surgical magnitude for lumbar surgery based on the changes in the IL-6 response. The serum IL-6 after laminectomy/PLF on the first day was significantly higher than that after laminotomy/open discectomy. This result suggests that the surgical magnitude of laminectomy/PLF was the most severe because of more extensive muscle detachment and the need for decortication. We also compared cervical laminoplasty with laminectomy/PLF from the viewpoint of the IL-6 response. The serum IL-6 after laminectomy/PLF was significantly higher than that after cervical laminoplasty. When comparing lumbar surgeries with cervical surgeries, even when the length of the skin incision is the same, the extent of soft tissue damage (e.g., depth of approach or muscle detachment) is different. IL-6 may reflect the surgical magnitude, including both the extent of the systemic response (e.g., CRP level) and the soft tissue damage (e.g., CK level). Based on the IL-6 response, cervical laminoplasty at four levels had almost the same surgical magnitude as lumbar laminotomy at a single level. Jakeways et al.17 and Maruszynski et al.19 reported less invasiveness of laparoscopic cholecystectomy based on the serum IL-6 response. Fornara et al.20 and Miyake et al.21 noted less traumatization during urological laparoscopic surgery. The IL-6 concentration on the first day might be also employed quantitatively to compare the surgical magnitude of minimally invasive spinal surgery versus conventional spinal surgery. Serum IL-6 has also been used as a marker for predicting complications during the postoperative period. Oka et al. showed a positive correlation between the peak IL-6 level and the incidence of postoperative complications following thoracoabdominal surgery.22 In our study, there were no postoperative complications. However, to predict such complications at an early point in time, it is important to understand the kinetics, or peak of IL-6 response, of each spinal surgery. Measurement of serum IL-6 might serve as an aid in predicting postoperative complications after spinal surgery. This study demonstrated that serum IL-6 concentration on the first day following surgery varied depending on the surgical procedure used. Hence, it might be used as a quantitative marker of surgical magnitude following spinal surgery.
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References 1. Fong Y, Moldawer LL, Shires GT, Lowry SF. The biologic characteristics of cytokines and their implication in surgical injury. Surg Gynecol Obstet 1990;170:363–78. 2. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 1999;340:448–54. 3. Sironi M, Breviario F, Proserpio P, Biondi A, Vecchi A, Van Damme J, et al. IL-1 stimulates IL-6 production in endothelial cells. J Immunol 1989;142:549–53. 4. Tosato G, Jones KD. Interleukin-1 induces interleukin-6 production in peripheral blood monocytes. Blood 1990;75:1305–10. 5. Elias JA, Lentz V. IL-1 and tumor necrosis factor synergistically stimulate fibloblast IL-6 production and stabilize IL-6 messenger RNA. J immunol 1990;145:161–6. 6. Kristiansson M, Saraste L, Soop M, Sundqvist KG, Thörne A. Diminished interleukin-6 and C-reactive protein responses to laparoscopic versus open cholecystectomy. Acta Anaesthesiol Scand 1999;43:146–52. 7. Le J, Vilcek J. Interleukin 6: a multifunctional cytokine regulating immune reactions and the acute phase protein response. Lab Invest 1989;61:588–602. 8. Sakamoto K, Arakawa H, Mita S, Ishiko T, Ikei S, Egami H, et al. Elevation of circulating interleukin 6 after surgery: factors influencing the serum level. Cytokine 1994;6:181–6. 9. Shenkin A, Fraser WD, Series J, Winstanley FP, McCartney AC, Burns HJG, et al. The serum interleukin6 response to elective surgery. Lymphokine Res 1989;8:123–7. 10. Cruickshank AM, Fraser WD, Burns HJG, Damme JV, Shenkin A. Response of serum interleukin-6 in patients undergoing elective surgery of varying severity. Clin Sci 1990;79:161–5. 11. Baigrie RJ, Lamont PM, Kwiatkowski D, Dallman MJ, Morris PJ. Systemic cytokine response after major surgery. Br J Surg 1992; 79:757–60. 12. He Z, Tonb DJ, Dabney KW, Miller F, Shah SA, Brenn BR, et al. Cytokine release, pancreatic injury, and risk of acute pancreatitis after spinal fusion surgery. Dig Dis Sci 2004;49:143–9. 13. Takahashi J, Ebara S, Kamimura S, Kinoshita T, Misawa H, Shimogata M, et al. Pro-inflammatory and anti-inflammatory cytokine increases after spinal instrumentation surgery. J Spinal Disord Tech 2002;15:294–300. 14. Kragsbjerg P, Holmberg H, Vikerfors T. Serum concentrations of interleukin-6, tumour necrosis factor-α, and C-reactive protein in patients undergoing major operations. Eur J Surg 1995;161:17–22. 15. Colley CM, Fleck A, Goode AW, Muller BR, Myers MA. Early time course of the acute phase protein response in man. J Clin Pathol 1983;36:203–7. 16. Stahl WM. Acute phase protein response to tissue injury. Crit Care Med 1987;15:545–50. 17. Jakeways MSR, Mitchell V, Hashim IA, Chadwick SJD, Shenkin A, Green CJ, et al. Metabolic and inflammatory responses after open or laparoscopic cholecystectomy. Br J Surg 1994;81:127–31. 18. Strecker W, Gebhard F, Rager J, Bruckner UB, Steinbach G, Kinzl L. Early biochemical characterization of soft-tissue trauma and fracture trauma. J Trauma 1999;47:358–64. 19. Maruszynski M, Pojda Z. Interleukin 6 (IL-6) levels in the monitoring of surgical trauma: a comparison of serum IL-6 concentrations in patients treated by cholecystectomy via laparotomy or laparoscopy. Surg Endosc 1995;9:882–5. 20. Fornara P, Doehn C, Seyfarth M, Jocham D. Why is urological laparoscopy minimally invasive? Eur Urol 2000;37:241–50. 21. Miyake H, Kawabata G, Gotoh A, Fujisawa M, Okada H, Arakawa S, et al. Comparison of surgical stress between laparoscopy and open surgery in the field of urology by measurement of humoral mediators. Int J Urol 2002;9:329–33. 22. Oka Y, Murata A, Nishijima J, Yasuda T, Hiraoka T, Ohmachi Y, et al. Circulating interleukin 6 as a useful marker for predicting postoperative complications. Cytokine 1992;4:298–304.
Original article Serum interleukin-6 response after spinal surgery: estimation of surgical magnitude Satoru Demura1,2, Keisuke Takahashi2, Norio Kawahara1, Yasuyuki Watanabe2, and Katsuro Tomita1 1 2
Department of Orthopaedic Surgery, Kanazawa University, 13-1 Takaramachi, Kanazawa 920-8641, Japan Department of Orthopedic Surgery, Saitama Medical School, Saitama, Japan
Abstract Background. Serum interleukin-6 (IL-6) has been used for quantitative estimation of the surgical magnitude of major cardiac and thoracoabdominal surgery, but there have been few studies assessing IL-6 as a marker of surgical magnitude of spinal surgery. Methods. We investigated the changes in IL-6 response in comparison to other parameters of surgical magnitude and spinal surgery procedures. The study included 40 patients electively undergoing spinal surgery. The patients were divided into four groups: lumbar laminectomy with posterolateral fusion (PLF), lumbar laminotomy, lumbar open discectomy, and cervical laminoplasty. Serum IL-6, C-reactive protein (CRP), creatine kinase (CK), and the white blood cell (WBC) count were determined in venous blood before surgery, at the end of surgery, and 6 h and the first, third, and seventh days after surgery. Results. Serum IL-6 peaked on the first day and returned to a normal value by the seventh day. The peak IL-6 concentrations on the first day after surgery significantly correlated with CRP, CK, duration of surgery, and estimated blood loss. Regarding lumbar surgeries, the peak IL-6 for laminectomy/ PLF was significantly higher than that for laminotomy/open discectomy or for cervical laminoplasty. Conclusions. Serum IL-6 on the first day varied depending on the surgical procedure used. Therefore, it might be a quantitative marker of surgical magnitude following spinal surgery.
Introduction Attempts to optimize and modify surgical methods are causing an increasing demand for simple, reliable tests that make it possible to evaluate the magnitude of damage resulting from the surgery. The estimation of surgical magnitude has so far been based on the length of the Offprint requests to: S. Demura Received: July 22, 2005 / Accepted: January 12, 2006
skin incision, duration of surgery, and estimated blood loss. These factors, however, do not always indicate the surgical magnitude because of the various local or systemic responses that occur after surgery. Surgical magnitude may be defined as the extent to which the factors that disrupt homeostasis are present. After surgery, immune cells such as macrophages and neutrophils or fibroblasts and endothelial cells are activated locally at the surgical site by the destruction of tissues, and they induce a systemic inflammatory response. The systemic response is controlled by a large number of mediators. The mediators include the proinflammatory cytokines: interleukin-1β (IL-1β), tumor necrosis factor-α (TNFα), and IL-6.1,2 TNFα and IL-1β, which enhance the production of IL-6,3–5 are mainly found at a surgical site and are seldom in peripheral blood,6 whereas IL-6 is more likely to be detected in peripheral blood because it has much longer half-life than IL-1β or TNFα. IL-6, which has many biological activities, such as induction of acute-phase proteins, immunoglobulin synthesis, activation of T cells, induction of ACTH synthesis, and increasing platelets,7 is one of the key mediators of the systemic inflammatory response. Sakamoto et al.8 showed that IL-6 concentration at the surgical site correlated with that in the peripheral blood but was markedly higher than in peripheral blood. It is conceivable that IL-6 in peripheral blood reflects the reaction of both the local and systemic responses. Clinically, the peak IL-6 concentration has been used as a marker of surgical magnitude after major cardiac and thoracoabdominal surgery,9–11 but the kinetics of the IL-6 concentration differs depending on the surgical procedure. There have been few studies assessing the kinetics of IL-6 after spinal surgery.12,13 Therefore, the aim of this study was to investigate the kinetics of IL-6, compare IL-6 to other parameters, and evaluate whether serum IL-6 is a quantitative marker of surgical magnitude after spinal surgery.
242
S. Demura et al.: IL-6 response after spinal surgery
Methods
Blood samples
Patients This study included 40 patients undergoing elective spinal surgery. There were 14 women and 26 men, with a median age of 57.5 years (27–77 years). The patients were divided into four groups according to surgical procedure: group I, laminectomy with posterolateral fusion (PLF) for lumbar degenerative spondylolisthesis (10 cases); group II, laminotomy for lumbar spinal stenosis (10 cases); group III, open discectomy for lumber disc herniation (10 cases); group IV, cervical laminoplasty cervical spondylotic myelopathy (9 cases) or cervical ossification of the posterior longitudinal ligament (1 case). No patients suffered from inflammatory conditions (e.g., rheumatoid arthritis) or were being treated with drugs, that are known to affect the acute-phase response. All patients gave informed consent for blood samples to be obtained for this study. Anesthesia and operative procedures All patients were premedicated with 0.5 mg atropine sulfate i.m. 30 min before introduction of anesthesia. General anesthesia was induced with thiopental sodium 5–7 mg/kg and maintained with nitrous oxide, oxygen, and sevoflurane (GOS). Neuromuscular block was achieved with vecuronium bromide. For postoperative analgesia, 15 mg pentazocine and 25–50 mg diclofenac sodium were administered. Laminectomy/PLF was performed at a single level without instrumentation. The resected bone of the spinous process and lamina with hydroxyapatite granules was used for the graft without harvesting iliac bone. Bilateral laminotomy was performed at a single disc level. Discectomy was also performed by small laminotomy at a single level. Unilateral open-door cervical laminoplasty with hydroxyapatite spacers was performed at four levels of the laminae from C3 to C6. We did not use a microscope during these surgeries.
Venous blood samples were obtained before surgery, at the end of surgery, 6 h after the end of surgery, and on the first, third, and seventh days after surgery. For IL-6, C-reactive protein (CRP), and creatine kinase (CK) measurements, samples were collected in heparinized tubes and immediately centrifuged at 3000 rpm for 10 min. They were then stored at −20°C until assayed. To determine the white blood cell (WBC) count, samples were collected in EDTA tubes and analyzed consecutively. Serum IL-6 was measured by enzyme immunoassay. The detection limits of this assay were 0.3 pg/ml for IL-6 and 0.10 mg/dl for CRP. The reference values were 4 pg/ml for IL-6, 0.25 mg/dl for CRP, and 24–195 U/l for CK. Statistical analysis Data on patient age, duration of surgery, and estimated blood loss are expressed as medians with ranges; other data are expressed as medians with 10%, 25%, 75%, and 90% percentiles. For comparison of unpaired values among groups, the Kruskal-Wallis test was used followed by the Scheffe test for multiple comparisons. For comparison of paired values, the Friedman test was used followed by the Wilcoxon test. The Spearman rank correlation test was used to test correlations between variables. P < 0.05 was considered significant. Statistical analysis was performed using the Stat View 5.0 statistical software.
Results The clinical data are summarized in Table 1. There was no significant difference with respect to age. The duration of surgery in group III was significantly shorter than that in the other groups, and that in group I was significantly longer than that in group II (P < 0.05). Estimated blood loss in group I was significantly more
Table 1. Classification of patients and their clinical data Group I II III IV
Surgical procedure
Sex (M/F)
Age (years)
Duration of surgery (min)
Estimated blood loss (ml)
Laminectomy + PLF (n = 10) Laminotomy (n = 10) Open discectomy (n = 10) Laminoplasty (n = 10)
3/7 7/3 8/2 7/3
63.5 (50–72) 64.5 (30–72) 50.0 (27–69) 57.5 (43–77)
181 (159–274)** 146 (110–195)*,** 101 (56–140)* 178 (127–240)
145 (70–240)# 90.0 (50–125)# 40.0 (5–70)## 128 (50–185)##
PLF, posterolateral fusion Values are the median and range *,** Significant differences of duration of surgery in each group (P < 0.05) #,## Significant differences of estimated blood loss in each group (P < 0.05)
S. Demura et al.: IL-6 response after spinal surgery
Fig. 1. Changes in serum interleukin-6 (IL-6) concentrations in 40 patients after spinal surgery. There was statistical significance for the time indicated vs. the preoperative value (*P < 0.05, Friedman and Wilcoxon tests). Data are expressed as the median with 25% and 75% (boxes) and 10% and 90% (error bars) percentiles. Preop, preoperatively; end-op, at the end of surgery
than that in group II or III, and that in group IV was significantly more than that in group III (P < 0.05). The median serum IL-6 concentrations before surgery in all groups were within the normal range (median 1.5 pg/ml, range 0.4–3.8 pg/ml). There was no correlation between the serum IL-6 before surgery and the patient’s age (r = 0.20, P = 0.13), and there was no correlation between the serum IL-6 level on the first postoperative day for each procedure and age (data not shown). In all groups, there was an increase in the serum IL-6 concentration after the end of surgery. The median serum IL-6 peaked on the first day after surgery (29.1 pg/ml, range 7.8–154.0 pg/ml) and decreased rapidly, normalizing by the seventh day (2.9 pg/ml, range 1.0–10.2 pg/ml) (Fig. 1). The median CRP concentrations peaked on the third day after surgery (5.4 mg/dl, range 0.78–18.5 mg/dl), decreased rapidly, but remained elevated on the seventh day (0.77 mg/dl, range 0.24– 4.7 mg/dl) (Fig. 2). The median WBC count peaked on the first day after surgery (9.5 × 10.03/mm3, range 5.8– 14.4 × 103/mm3), decreased moderately, and normalized on the seventh day (5.7 × 10.03/mm3, range 1.8–8.4 × 103/ mm3) (Fig. 3). The median CK level peaked on the first day after surgery (473 U/l, range 127–1931 U/l) and returned to preoperative the value by the seventh day (63 U/l, range 25–341 U/l) (Fig. 4). The median IL-6 concentrations for the four groups (surgical procedures) on the first postoperative day were 85.0 pg/ml (range 18.3–154.0 pg/ml) in group I, 29.1 pg/ml (range 13.0–65.3 pg/ml) in group II, 17.5 pg/
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Fig. 2. Changes in serum C-reactive protein (CRP) concentrations in 40 patients after spinal surgery. There was statistical significance for the times indicated vs. the preoperative value (*P < 0.05, Friedman and Wilcoxon tests). Data are expressed as the median with 25% and 75% (boxes) and 10% and 90% (error bars) percentiles
Fig. 3. Changes in white blood cell (WBC) counts (×103/mm3) in 40 patients after spinal surgery. There was statistical significance for the time indicated vs. the preoperative value (*P < 0.05, Friedman and Wilcoxon tests). Data are expressed as the median with 25% and 75% (boxes) and 10% and 90% (error bars) percentiles
ml (range 7.8–40.8 pg/ml) in group III, and 27.6 pg/ml (range 15.6–50.8 pg/ml) in group IV. The peak serum IL-6 concentration in group I was significantly higher than that in each of the other groups (P < 0.05); thus, these levels varied according to the surgical procedure (Fig. 5). The peak CRP level in group I was higher than
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Fig. 4. Changes in creative kinase (CK) concentrations in 40 patients after spinal surgery. There was statistical significance for the times indicated vs. the preoperative value (*P < 0.05, Friedman and Wilcoxon tests). Data are expressed as the median with 25% and 75% (boxes) and 10% and 90% (error bars) percentiles
Fig. 5. Serum interleukin-6 (IL-6) concentrations on the first day after spinal surgery. Group I, laminectomy with posterolateral fusion (PLF); group II, laminotomy; group III, open discectomy; group IV, cervical laminoplasty. There was statistical significance for group I vs. groups II–IV (*P < 0.05, Kruskal-Wallis and Scheffe tests). Data are expressed as the median with 25% and 75% (boxes) and 10% and 90% (error bars) percentiles
that in group III (P < 0.01) but did not differ from that in groups II and IV (Fig. 6). The peak WBC count did not differ among groups (Fig. 7). The peak CK level was higher in group I than in group III (P = 0.02) but did not differ from those in groups II and IV (Fig. 8).
S. Demura et al.: IL-6 response after spinal surgery
Fig. 6. Serum CRP concentrations on the third day after spinal surgery. There was statistical significance for group I vs. group III (*P < 0.05, Kruskal-Wallis and Scheffe tests). Data are expressed as the median with 25% and 75% (boxes) and 10% and 90% (error bars) percentiles
Fig. 7. WBC count on the first day after spinal surgery. Data are expressed as the median with 25% and 75% (boxes) and 10% and 90% (error bars) percentiles
We examined the correlation between peak serum IL-6 and other parameters. The peak IL-6 concentrations on the first day after surgery correlated well with the duration of surgery (r = 0.46, P = 0.004) and estimated blood loss (r = 0.77, P < 0.001) (Fig. 9A,B). There were significant correlations between the serum IL-6 concentration on the first day and the serum CRP level on the third day (r = 0.55, P = 0.001) (Fig. 9C) and the CK level on the first day (r = 0.50, P = 0.006) (Fig. 9E). The WBC count on the first day after surgery did not
S. Demura et al.: IL-6 response after spinal surgery
Fig. 8. CK concentrations on the first day after spinal surgery. There was statistical significance for group I vs. group III (*P < 0.05, Kruskal-Wallis and Scheffe tests). Data are expressed as the median with 25% and 75% (boxes) and 10% and 90% (error bars) percentiles
correlate with the serum IL-6 concentration on the first day (Fig. 9D). The CRP concentrations on the third day after surgery had good correlation with estimated blood loss (r = 0.50, P = 0.003) but not with the duration of surgery (r = 0.29, P = 0.078). The WBC count did not correlate with the estimated blood loss (r = −0.01, P = 0.95) and the duration of surgery (r = −0.10, P = 0.41).
Discussion The kinetics of the IL-6 concentration differs among surgical procedures. Shenkin et al.9 demonstrated that serum IL-6 concentrations reached a peak 1.5–4.0 h after surgery for elective cholecystectomy. Baigrie et al.11 showed that peak IL-6 concentrations occurred at 4–48 h with elective aortic surgery and then fell sharply from 48 to 72 h. For joint replacement surgery, Kragsbjerg et al.14 showed that peak IL-6 concentrations occurred 6–24 h after surgery. He et al.12 and Takahashi et al.13 showed that the peak IL-6 concentration occurred on the first day after spinal instrumentation surgery. In our series of spinal surgeries, serum IL-6 increased at the end of surgery, reached a peak on the first day, and had normalized by the seventh day. We confirmed that serum IL-6 on the first postoperative day was a quantitative marker for comparing spinal surgeries. It took a longer time to normalize the IL-6 concentration after spinal surgery than after abdominal or cardiac surgery. In most cases of spinal surgery, a part of the bone must be excised or the epidural space
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treated — either being a cause of prolonged postoperative hemorrhage that might require a longer period for the IL-6 to normalize. The CRP level reflects the extent of systemic response and has been used as a marker of surgical magnitude.15,16 Our results showed a significant correlation between the peak serum IL-6 level and the peak serum CRP level and that the peak IL-6 concentrations were seen earlier than the peak CRP concentrations, as shown in previous reports.10,14,17 It has been reported that IL-6 is a mediator of CRP synthesis in the liver.1,2 The results of this study suggest that IL-6 is an early marker of the systemic response after spinal surgery as well. Strecker et al. reported that the CK level reflects the extent of soft tissue damage in trauma patients.18 It is suggested that CK serves to indicate the extent of tissue damage according to the surgery performed. In this study, there was a significant correlation between the serum IL-6 level and the CK level on the first day, which indicates the possibility that IL-6 is reflecting the severity of local tissue damage due to the spinal surgery. It is thought that most postoperative increases in the WBC count correlate with the increases in neutrophil counts. Although neutrophil activation is controlled by various cytokines, glanulocyte colony stimulating factor mainly activates neutrophils from bone marrow to peripheral blood. In this study, IL-6 and the WBC count were the markers showing an earlier response than that indicated by the CRP level. The peak WBC count, however, did not differ among the various types of surgery. Thus, the WBC count may not be sufficiently sensitive to be a marker to show the extent of a postoperative systemic response. Many reports have assessed surgical magnitude based on duration of surgery and estimated blood loss. Shenkin et al.9 and Sakamoto et al.8 reported that serum IL-6 correlated well with the duration of surgery and estimated blood loss. It is true that the peak IL-6 concentrations correlated with these factors for most of our spinal surgery. When we compare surgical magnitude using the same surgical procedure, the duration of surgery and estimated blood loss may serve as quantitative markers. However, when comparing laminectomy/PLF and cervical laminoplasty, the peak IL-6 differed significantly, although the duration of the surgery and the estimated blood loss were almost the same. Therefore, if surgical sites differ, it might be difficult to estimate the surgical magnitude by surgery duration or estimated blood loss alone. Furthermore, it may be impossible to compare the surgical magnitude between microscopic spine surgery (which has a long duration with minimal blood loss) and spine surgery such as excision of a hypervascular tumor (which is associated with excessive bleeding and short surgery duration). IL-6 might be
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S. Demura et al.: IL-6 response after spinal surgery
A
B
C
D
E Fig. 9. A Correlation between peak serum IL-6 concentrations and the duration of surgery. The peak serum IL-6 concentrations significantly correlated with the duration of surgery (Spearman rank correlation test). B Correlation between peak serum IL-6 concentrations and estimated blood loss. The peak serum IL-6 concentrations strongly correlated with estimated blood loss (Spearman rank correlation test). C Correlation between peak serum IL-6 concentrations and peak serum CRP concentrations. The peak serum IL-6 con-
centrations significantly correlated with the peak serum CRP concentrations (Spearman rank correlation test). D Correlation between peak serum IL-6 concentrations and the WBC count on the first day. There was no significant correlation (Spearman rank correlation test). E Correlation between peak serum IL-6 concentrations and peak CK concentrations. The peak serum IL-6 concentrations significantly correlated with the peak CK concentrations (Spearman rank correlation test)
S. Demura et al.: IL-6 response after spinal surgery
reflecting surgical magnitude independent of the estimated blood loss or duration of surgery. These results indicate that the serum IL-6 level reflects both the local and systemic responses, that is, the surgical magnitude during spinal surgery. Peak IL-6 has been used as an index of surgical magnitude for cardiovascular and thoracoabdominal surgery. Cruickshank et al.10 and Kragsbjerg et al.14 showed that the peak IL-6 level differed among surgical procedures and was a sensitive marker of surgical magnitude. We compared surgical magnitude for lumbar surgery based on the changes in the IL-6 response. The serum IL-6 after laminectomy/PLF on the first day was significantly higher than that after laminotomy/open discectomy. This result suggests that the surgical magnitude of laminectomy/PLF was the most severe because of more extensive muscle detachment and the need for decortication. We also compared cervical laminoplasty with laminectomy/PLF from the viewpoint of the IL-6 response. The serum IL-6 after laminectomy/PLF was significantly higher than that after cervical laminoplasty. When comparing lumbar surgeries with cervical surgeries, even when the length of the skin incision is the same, the extent of soft tissue damage (e.g., depth of approach or muscle detachment) is different. IL-6 may reflect the surgical magnitude, including both the extent of the systemic response (e.g., CRP level) and the soft tissue damage (e.g., CK level). Based on the IL-6 response, cervical laminoplasty at four levels had almost the same surgical magnitude as lumbar laminotomy at a single level. Jakeways et al.17 and Maruszynski et al.19 reported less invasiveness of laparoscopic cholecystectomy based on the serum IL-6 response. Fornara et al.20 and Miyake et al.21 noted less traumatization during urological laparoscopic surgery. The IL-6 concentration on the first day might be also employed quantitatively to compare the surgical magnitude of minimally invasive spinal surgery versus conventional spinal surgery. Serum IL-6 has also been used as a marker for predicting complications during the postoperative period. Oka et al. showed a positive correlation between the peak IL-6 level and the incidence of postoperative complications following thoracoabdominal surgery.22 In our study, there were no postoperative complications. However, to predict such complications at an early point in time, it is important to understand the kinetics, or peak of IL-6 response, of each spinal surgery. Measurement of serum IL-6 might serve as an aid in predicting postoperative complications after spinal surgery. This study demonstrated that serum IL-6 concentration on the first day following surgery varied depending on the surgical procedure used. Hence, it might be used as a quantitative marker of surgical magnitude following spinal surgery.
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