The activation of the cytokine network is crucial for acute-phase response to stimuli such as surgical stress [1]. Surgical trauma can stimulate acute-phase response, which is thought to be mediated by cytokines including interleukin (IL)-6, IL-8, tumor necrosis factor-a (TNF-a), and C-reactive protein (CRP). Serum IL-6 level was identified as a sensitive early marker of tissue damage, and was found to be correlated with the severity of trauma, blood loss, and duration of surgical procedures [2][3][4]. Moreover, significant surgical trauma has been associated with increased IL-6 response [5]. Compared to other available markers, IL-6 showed better correlation with the magnitude of injury and systemic inflammatory response [6].

In head and neck otolaryngology, various surgical procedures are employed. These procedures have been associated with a wide range of surgical stress. For instance, laryngeal microsurgery (LMS) and endoscopic sinus surgery (ESS), which require no incision of the skin, may induce less inflammatory response when compared to head and neck cancer surgery using the microvascular free flap reconstruction technique. Currently, minimally invasive surgery techniques are preferred and widely accepted. However, to best of our knowledge, no studies have been performed to objectively compare surgical stress among various otolaryngology head and neck surgeries. In the present study, we evaluated serum IL-6 level at early postoperative period following otolaryngology head and neck surgery to investigate the postoperative stress response and assess surgical stress in head and neck otolaryngology.

Venous blood samples were obtained from patients upon admission and 24 h after surgery. Serum was isolated and stored at -80°C. Venous blood samples 24 h before surgery were also obtained from 15 patients.

Interleukin-6 level was analyzed using a commercially available solid-phase sandwich enzyme-linked immunosorbent assay (ELISA) kit with an IL-6 monoclonal antibody (R&D Systems Co, Minneapolis, MN, USA). Serum CRP level was measured and analyzed at the Department of Laboratory Diagnosis, Sapporo Medical University. Furthermore, duration of surgery was recorded and intraoperative blood loss was evaluated.

Statistical analysis was performed using SPSS version 22 (IBM Analytics, Armonk, NY, USA). Differences between groups were assessed using the Tukey–Kramer method. Correlations between variables were evaluated using the Spearman’s rank correlation coefficient. Data are expressed as the mean ± standard deviation. p values of pf < 0.05 were considered statistically significant.

There was a significant correlation between the duration of surgery and serum IL-6 level ( (Figure 1); Spearman’s rank correlation test: rs = 0.611; p < 0.01). Blood loss was also significantly correlated with serum IL-6 level (Figure 2), Spearman’s rank correlation test: rs = 0.742, p < 0.01.

C-reactive protein has been widely used as an early marker for inflammatory response. The correlation between serum CRP level and IL-6 concentration 24 h after surgery is shown in (Figure 3). There was a significant correlation between serum CRP and IL-6 levels (Figure 3; Spearman’s rank correlation test: rs = 0.496; p < 0.01).

The preoperative serum IL-6 level obtained from 23 patients was 0.85±0.77 pg/ml. The postoperative serum IL-6 level at 24 h post-surgery for each patient group is shown in (Figure 4). Serum IL-6 level in the ear, nose, and larynx group was 8.6 ± 5.9, 32.4±20.2, and 4.6±3.9 pg/ml, respectively. Interleukin-6 level for the tonsil group was 12.2±8.5 pg/ml, whereas the level for the Adenoid and tonsil group was 24.8±24.7 pg/ml. Interleukin-6 level for the parotid gland and thyroid groups was 18.5±12.4 and 25.9±21.9 pg/ml, respectively. Serum IL-6 level was significantly higher in the HNT than other groups, with the HNT-1 and HNT-2 groups displaying 100.5±86.7 and 285.8 ± 187.1 pg/ml of serum IL-6, respectively. No significant differences in serum IL-6 level were observed between groups, except for the HNT-1 and -2 groups.

Various surgical procedures are utilized in otorhinolaryngology. Interleukin-6 activation is known to play a role during acute response to operative trauma [2][3] [4]. The present study is the first to evaluate surgical stress associated with otolaryngology head and neck surgeries by analyzing serum IL-6 level during early postoperative period.

Serum IL-6 level has been acknowledged as an indicator of surgical stress [7] [8][9]. Although TNF-a and IL-8 were also thought to mediate acute-phase response due to surgical trauma, they were not detected in significant amount or their levels were below the limit of detection by ELISA in the present study. Interleukin-6 is produced by activated monocytes, macrophages, T cells, B cells, epithelial cells, and fibroblasts as an acute phase protein during operative damage [10]. Interleukin-6 production at surgical wound site has been reported and its level increased rapidly and peaked at 24 h after surgery [11][12]. Elevated serum IL-6 level resulting from local production was thought to reflect the degree of surgical damage and cause a systemic immunological effect [13]. Thus, serum IL-6 level can be utilized as an early and sensitive marker of surgical tissue damage [7][14].

Interleukin-6 and CRP were described to correlate with the severity of trauma, blood loss, and the duration of surgery [2]. Our results demonstrated a significant correlation between serum IL-6 and CRP levels. IL-6 induces the maturation of B-cell lymphocytes and synthesis of acute phase proteins including CRP in the liver [15]. Duration of surgical procedures and amount of blood loss were also shown to influence the degree of surgical damage [16]. Although changes in CRP or IL-6 levels may be induced by blood loss only, the amount of bleeding is generally thought to be proportional to surgical invasion. Indeed, in the present study, serum IL-6 level was also significantly correlated with blood loss and duration of surgery, and the extent of surgical stress was affected by these parameters. Our data revealed that serum IL-6 level can be used as a marker for surgical stress associated with otolaryngology head and neck surgery.

Otolaryngology head and neck surgeries comprise various surgical procedures that may be associated with surgical stress. As expected, the larynx group (LMS) showed the lowest serum IL-6 level, whereas the two HNT groups showed significantly higher IL-6 level when compared to other groups. Although low serum IL-6 level was also observed in the Tonsil group, adenoidectomy increased the IL-6 level approximately two-folds. No significant difference in surgery duration was observed between the HNT-1 and ear groups; however, the HNT-1 group displayed 7.6-fold increase in blood loss when compared to the ear group. In addition, the HNT-2 group showed approximately two-fold increase in surgery time and blood loss when compared to the HNT-1 group. The degree of surgical stress is known to be affected by surgery length and blood loss [16], which was reflected by the level of IL-6. Microvascular free flap reconstructions, which are considered more invasive, were included in the HNT-2 group. Elevated concentration of serum inflammatory cytokines has been reported in major and invasive surgical procedures. This revealed a close relationship between the invasion of cavities and severity of tissue damage [17][18][19]. Surgical procedures in the HNT-2 group may cause more extensive tissue injury and consequently a greater release of IL-6.

Measurement of serum interleukin-6 level is a valuable indicator to evaluate the degree of surgical stress in otolaryngology head and neck surgeries, because it is measurable and can be observed as a single peak of induction at early times following surgery.

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