Effect of sevoflurane pretreatment combined with propofol on cerebral oxygen metabolism and inflammatory response during one-lung ventilation

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1 Journal of Hainan Medical University 2017; 23(9): Journal of Hainan Medical University Effect of sevoflurane pretreatment combined with propofol on cerebral oxygen metabolism and inflammatory response during one-lung ventilation Yu-Li Liu, Xue-Yin Shi Anesthesiology Department, Changzheng Hospital Affiliated to Second Military Medical University, Shanghai, ARTICLE INFO Article history: Received 14 Apr 2017 Received in revised form 17 Apr 2017 Accepted 19 Apr 2017 Available online 24 May 2017 Keywords: One-lung ventilation Sevoflurane Cerebral oxygen metabolism Inflammatory response ABSTRACT Objective: To study the effect of sevoflurane pretreatment combined with propofol on cerebral oxygen metabolism and inflammatory response during one-lung ventilation. Methods: A total of 92 patients who accepted pulmonary lobectomy under one-lung ventilation in Changzheng Hospital Affiliated to Second Military Medical University between August 2014 and March 2016 were selected and divided into sevoflurane group and control group. Before one-lung ventilation (T1), 30 min after one-lung ventilation (T2) and 60 min after one-lung ventilation (T3), cerebral oxygen metabolism indexes and serum inflammation indexes were determined; after surgical resection, the lung tissue was collected to determine the expression of inflammatory signaling molecules and hypoxia injury molecules. Results: CjvO 2 and ajddco 2 levels as well as serum ICAM-1, IL-1β and TNF-α contents were not significantly different between two groups of patients at T1; CjvO 2 levels as well as serum ICAM-1, IL-1β and TNF-α contents of sevoflurane group at T2 and T3 were significantly lower than those of control group while ajddco 2 levels were significantly higher than those of control group; after surgical resection, TLR4, NF-kB, AQP-4, p38mapk, HO-1, GLUT-1, HIF-1 毩 and CHOP protein expression in lung tissue of sevoflurane group were significantly lower than those of control group. Conclusion: Sevoflurane pretreatment combined with propofol can improve the cerebral oxygen metabolism and inhibit the inflammatory response during one-lung ventilation. 1. Introduction One-lung ventilation is the preferred way of ventilation for thoracic esophageal cancer surgery and lobectomy surgery, which can create a good space for the affected-side surgical operation, and also prevent pollution in the contralateral lung[1,2]. However, in the process of one-lung ventilation, the airway resistance increases significantly and the compliance decreases significantly in ventilation-side lung, and there is the pulmonary arteriovenous shunt caused by operation squeezing to local tissue, which will cause the ventilation/blood flow imbalance and hypoxic local vasoconstriction[3]. Alveolar is where the mononuclear macrophages, neutrophils and other inflammatory cells assemble, Corresponding author: Xue-Yin Shi, Anesthesiology Department, Changzheng Hospital Affiliated to Second Military Medical University, Shanghai, Tel: Fund Project: Natural Science Foundation of China No: and the ventilation/blood flow imbalance and local ischemia hypoxia caused by one-lung ventilation will significantly activate inflammatory response, cause local lung tissue damage, and then affect the alveoli oxygenation function and oxygen supply for important organs[4,5]. Sevoflurane is the inhaled anesthetic widely used in general anesthesia in recent years, it not only has good anesthesia maintenance effect, but also has inhibitory effect on the airway inflammation, and it shows positive application value in the process of one-lung ventilation. In the following study, the effect of sevoflurane pretreatment combined with propofol on cerebral oxygen metabolism and inflammatory response during one-lung ventilation was analyzed. 2. Research subjects and anesthesia methods 2.1Research subjects

2 148 A total of 92 patients who accepted pulmonary lobectomy under one-lung ventilation in Changzheng Hospital Affiliated to Second Military Medical University between August 2014 and March 2016 were selected as the research subjects, all the patients were in line with the pulmonary lobectomy indications, they were with preoperative ASA I-II grade and cardiac function I-II grade, and the patients with the history of respiratory infection and patients taking immune preparations 1 months before operation were ruled out. Random number table method was used to divide the 92 patients into sevoflurane group and control group (n=46). Sevoflurane group included 28 male cases and 18 female cases that were years old; control group included 25 male cases and 21 female cases that were years old. The two groups of patients were not significantly different in general data (P>0.05). 2.2Anesthesia methods Two groups of patients received routine intramuscular injection of phenobarbital 100 mg half an hour before operation, and after patients entered into the operating room, venous channel was usually opened, ECG monitoring was connected, and the heart rate, blood pressure, blood oxygen saturation and bispectral index were monitored. Anesthesia induction was as following: intravenous injection of midazolam 0.05 mg/kg, propofol 1.5 mg/kg, sufentanil 0.5 μg/kg and cis atracurium 0.2 mg/kg in turn. After anesthesia induction, double-lumen endotracheal intubation was conducted for controlled double-lung ventilation, and then the following method was followed to maintain anesthesia: (1) sevoflurane group: micro pump injection of propofol 2 μg/ml to maintain anesthesia, cis atracurium 0.03 mg/kg if necessary, sevoflurane inhalation, 30 min before one-lung ventilation, and maintaining the concentration at a minimum alveolar effective concentration; (2) control group: micro pump injection of propofol 2 μg/ml to maintain anesthesia, and cis atracurium 0.03 mg/kg if necessary. 2.3 Research methods Cerebral oxygen metabolism index detection methods Before one-lung ventilation (T1), 30 min after one-lung ventilation (T2) and 60 min after one-lung ventilation (T3), internal jugular vein bulb blood and radial artery blood were collected synchronously to detect internal jugular vein bulb partial pressure of oxygen (PjvO 2 ) and radial arterial partial pressure of oxygen (PaO 2 ), and the internal jugular vein bulb blood oxygen content (CjvO 2 ) and arterial-internal jugular vein bulb blood oxygen content difference (ajddco 2 ) were calculated Inflammatory response index detection methods At T1, T2 and T3, 5 ml cubital venous blood was collected and centrifuged to separate serum, and enzyme-linked immunosorbent assay kits were used to determine ICAM-1, IL-1β and TNF-α levels; after surgical resection, normal lung tissue was collected from the edge of removed lesions, the protein lysis buffer was used to extract the total protein in the tissue, and then enzyme-linked immunosorbent assay kits were used to determine TLR4, NF-kB, AQP-4, p38mapk, HO-1, GLUT-1, HIF-1α and CHOP levels. 2.4 Statistical methods SPSS 17.0 software was used for statistical analysis, analysis of cerebral oxygen metabolism indexes and inflammatory response indexes between two groups was by t test and P<0.05 indicated statistical significance in differences. 3.Results 3.1 Cerebral oxygen metabolism indexes of two groups of patients At T1, T2 and T3, analysis of cerebral oxygen metabolism indexes CjvO 2 and ajddco 2 between two groups of patients was as follows: CjvO 2 and ajddco 2 levels were not significantly different between two groups of patients at T1, CjvO 2 levels of sevoflurane group at T2 and T3 were significantly lower than those of control group while ajddco 2 levels were significantly higher than those of control group. The differences in CjvO 2 and ajddco 2 levels were statistically significant between two groups of patients (P<0.05). Table 1. Comparison of cerebral oxygen metabolism indexes between two groups of patients at different points in time (ml/l). Groups n Time point CjvO 2 ajddco 2 Sevoflurane group 46 T ± ±7.86 T ±22.14 * 54.76±7.83 * T ±17.68 * 58.14±7.91 * Control group 46 T ± ±8.94 T ± ±6.27 T ± ±6.78 * : comparison between sevoflurane group and control group at the same point in time, differences were statistically significant, P<0.05.

3 149 Table 2. Comparison of inflammatory response indexes in lung tissue between two groups of patients (ng/ml). Groups n TLR4 NF- 毷 B AQP-4 p38mapk Sevoflurane group ± ± ± ±0.93 Control group ± ± ± ±1.66 T P <0.05 <0.05 <0.05 <0.05 Table 3. Comparison of serum inflammatory response products between two groups of patients at different points in time. Groups n Time point ICAM-1 IL-1β TNF-α Sevoflurane group 46 T ± ± ±0.89 T ±36.75 * 15.42±1.99 * 8.31±1.14 * T ±42.15 * 17.03±2.42 * 9.65±1.32 * Control group 46 T ± ± ±0.91 T ± ± ±1.76 T ± ± ±2.52 * : comparison between sevoflurane group and control group at the same point in time, differences were statistically significant, P< Inflammatory response indexes of two groups of patients CHOP protein expression in lung tissue were statistically significant between two groups of patients (P<0.05). After surgical resection, analysis of inflammatory response molecules TLR4, NF-kB, AQP-4 and p38mapk protein expression in lung tissue was as follows: TLR4, NF-kB, AQP-4 and p38mapk protein expression in lung tissue of sevoflurane group were significantly lower than those of control group; at T1, T2 and T3, analysis of serum inflammatory response products ICAM-1 (pg/ ml), IL-1β (ng/ml) and TNF-α (ng/ml) contents was as follows: serum ICAM-1, IL-1β and TNF-α contents were not significantly different between two groups of patients at T1, and serum ICAM-1, IL-1β and TNF-α contents of sevoflurane group at T2 and T3 were significantly lower than those of control group. Differences in TLR4, NF-kB, AQP-4 and p38mapk protein expression in lung tissue as well as serum ICAM-1, IL-1β and TNF-α contents at T2 and T3 were statistically significant between two groups of patients (P<0.05). 3.3Hypoxia-related indexes of two groups of patients After surgical resection, analysis of hypoxia-related indexes HO-1, GLUT-1, HIF-1 毩 and CHOP expression in lung tissue was as follows: HO-1, GLUT-1, HIF-1 毩 and CHOP protein expression in lung tissue of sevoflurane group were significantly lower than those of control group. Differences in HO-1, GLUT-1, HIF-1 毩 and 4.Discussion In the process of one-lung ventilation, alveolar ventilation/blood flow imbalance and oxygenation injury will directly affect the blood supply of important organs, brain tissue is extremely sensitive to ischemia hypoxia, and intraoperative ventilation function change and hemodynamic fluctuations can affect the cerebral oxygen metabolism and cause brain tissue oxygen supply and oxygen demand imbalance[6,7]. CjvO 2 and ajddco 2 are the common indicators to evaluate cerebral oxygen metabolism, the cerebral ischemia hypoxia state will affect the cerebral blood flow, oxygen uptake and utilization, etc., which will lead to increased CjvO 2 and decreased ajddco 2, and indicates that the oxygen absorbed by brain tissue decreases and the oxygen flowing back to the internal jugular vein increases[8,9]. Sevoflurane is the inhalation anesthetic that has been increasingly used in general anesthesia in recent years, and it not only has good anesthesia maintenance effect, but can also protect airway function[10-12]. In order to define the protective effect of sevoflurane pretreatment combined with propofol on lung tissue during one-lung ventilation, alveolar oxygenation function was analyzed at first in the study, and analysis of cerebral oxygen metabolism indexes showed that CjvO 2 levels of sevoflurane group Table 4. Comparison of hypoxia-related indexes in lung tissue between two groups of patients (ng/ml). Groups n HO-1 GLUT-1 HIF-1 毩 CHOP Sevoflurane group ± ± ± ±0.78 Control group ± ± ± ±1.79 T P <0.05 <0.05 <0.05 <0.05

4 150 at T2 and T3 were significantly lower than those of control group while ajddco 2 levels were significantly higher than those of control group. This means that in the process of one-lung ventilation, the cerebral oxygen supply and oxygen demand are in balance and there is no obvious oxygen uptake or utilization obstacle in sevoflurane group of patients, and sevoflurane pretreatment can reduce the influence of one-lung ventilation on alveolar oxygenation function and cerebral oxygen metabolism. Alveolus is where mononuclear macrophages, neutrophils and other inflammatory cells assemble, and the ventilation/blood flow imbalance and local ischemia hypoxia during one-lung ventilation can activate the inflammation through multiple signaling pathways to cause the alveolar damage and influence oxygenation function[13,14]. TLR4 is an important pattern recognition receptor in the body to regulate inflammation, and hypoxia stimulation can increase the expression of TLR4 to activate the NF-kB through downstream adaptor molecule MyD88, and then start the expression of a variety of inflammatory factors; AQP-1 is the transport protein that adjusts the alveolar and vascular endothelial water permeability, and it can increase the infiltration of inflammatory cells in local area; p38mapk is one of the molecules of the MAPK family, and it can initiate the expression of a variety of inflammatory cytokines through the phosphorylation of the downstream molecules[15,16]. In order to define the effect of sevoflurane on alveolus inflammation during one-lung ventilation, the expression levels of these signal pathway molecules in lung tissue were analyzed in the study, and the results showed that TLR4, NF-kB, AQP-4 and p38mapk protein expression in lung tissue of sevoflurane group were significantly lower than those of control group. This means that sevoflurane can inhibit the inflammation mediated by TLR4, AQP 1 and p38mapk pathway during one-lung ventilation. The activation of inflammatory response mediated by TLR4, AQP-1 and p38mapk pathway in alveoli during one-lung ventilation can increase the expression and secretion of a variety of inflammatory cytokines. ICAM-1, IL-1β and TNF-α are the important cytokines causing alveolus inflammation, ICAM-1 can promote inflammatory cell adhesion with alveolar epithelial cells and vascular endothelial cells, and then infiltrate and accumulate in the alveoli; IL-1β and TNF-α are secreted by the infiltrated and activated mononuclear macrophages, and they can not only cause alveolar inflammatory injury, but also mediate cascade amplification of inflammatory response. In the study, analysis of above serum inflammatory reaction product levels showed that serum ICAM-1, IL-1β and TNF-α contents were not significantly different between two groups of patients at T1, and serum ICAM-1, IL-1β and TNF-α contents of sevoflurane group at T2 and T3 were significantly lower than those of control group. This further confirms that sevoflurane can inhibit the inflammatory reaction during one-lung ventilation, and serum inflammatory cytokine contents after one-lung ventilation were not significantly higher than those before one-lung ventilation. The inflammatory response caused by ventilation/blood flow imbalance and local ischemia hypoxia can cause lung tissue damage, and HO-1, GLUT-1, HIF-1 毩, CHOP and other molecules have played a key role in lung tissue injury caused by hypoxia. HO-1 is the endogenous protective protein to regulate oxidative stress reaction, and it has antioxidant and anti-ischemia-reperfusion injury effect[17]; GLUT-1 is a member of the glucose transporter family, it is involved in the regulation of intracellular and extracellular passive glucose transport and mitochondrial function, and under the hypoxia condition, it can increase intracellular glucose concentration and guarantee the energy needed by cell metabolism; HIF-1 毩 is a type of transcription factor induced by hypoxia conditions, its compensatory expression increases in hypoxia state and it can adjust the expression of a variety of downstream genes to enhance the ability of local tissue to endure hypoxia injury[18]; CHOP is a sign of endoplasmic reticulum stress, hypoxia can aggravate the endoplasmic reticulum stress, lead to the unfolded and misfolded protein accumulation, and also increase the expression of CHOP. In order to define the effect of sevoflurane on the lung tissue damage caused by hypoxia during one-lung ventilation, the expression levels of these molecules in the lung tissue were analyzed, and the results showed that HO-1, GLUT-1, HIF-1 毩 and CHOP protein expression in lung tissue of sevoflurane group were significantly lower than those of control group. This means that sevoflurane can reduce the lung tissue damage mediated by HO-1, GLUT-1, HIF-1α and CHOP pathways during one-lung ventilation. To sum up, it is believed that sevoflurane pretreatment combined with propofol for one-lung ventilation can improve alveolar oxygenation function and cerebral oxygen metabolism, and inhibit the inflammation activation and hypoxia-induced injury in lung tissue. References [1] Neto AS, Hemmes SN, Barbas CS, Beiderlinden M, Fernandez- Bustamante A, Futier E, et al. Association between driving pressure and development of postoperative pulmonary complications in patients undergoing mechanical ventilation for general anaesthesia: a metaanalysis of individual patient data. Lancet Respir Med 2016; 4(4): [2] Downs JB, Robinson LA, Steighner ML, Thrush D, Reich RR, Rasanen JO. Open lung ventilation optimizes pulmonary function during lung surgery. J Surg Res 2014; 192(2): [3] Tian Y, Gawlak G, O'Donnell JJ 3rd, Mambetsariev I, Birukova AA. Modulation of endothelial inflammation by low and high magnitude

5 151 cyclic stretch. PLoS One 2016; 11(4): e [4] Retamal J, Borges JB, Bruhn A, Feinstein R, Hedenstierna G, Suarez- Sipmann F, et al. Open lung approach ventilation abolishes the negative effects of respiratory rate in experimental lung injury. Acta Anaesthesiol Scand 2016; 60(8): [5] Barton SK, Tolcos M, Miller SL, Christoph-Roehr C, Schmolzer GM, Moss TJ, et al. Ventilation-induced brain injury in preterm neonates: a review of potential therapies. Neonatology 2016; 110(2): [6] Baumgardner JE, Hedenstierna G. Ventilation/perfusion distributions revisited. Curr Opin Anaesthesiol 2016; 29(1): 2-7. [7] Brassard CL, Lohser J, Donati F, Bussieres JS. Step-by-step clinical management of one-lung ventilation: continuing professional development. Can J Anaesth 2014; 61(12): [8] Yasuuji M, Kusunoki S, Hamada H, Kawamoto M. Intermittent reinflation is safe to maintain oxygenation without alteration of extravascular lung water during one-lung ventilation. J Clin Anesth 2014; 26(3): [9] Bassingthwaighte JB, Raymond GM, Dash RK, Beard DA, Nolan M. The pathway for oxygen: tutorial modelling on oxygen transport from air to mitochondrion: the pathway for oxygen. Adv Exp Med Biol 2016; 876: [10] Potocnik I, Novak Jankovic V, Sostaric M, Jerin A, Stupnik T, Skitek M, et al. Antiinflammatory effect of sevoflurane in open lung surgery with one-lung ventilation. Croatian Med J 2014; 55(6): [11] Feng H, Wang GM, Qiao Y, Zhao X, Liu DY, Ding YL, et al. Effects of sevoflurane preconditioning on lung injury during one lung ventilation. Int J Clin Exp Med 2015; 8(8): [12] Tao Hongxia, Shen Qiying, Li Yuanhai. Effect of sevoflurane preconditioning on lung compliance and oxygenation index during one lung ventilation. Acta Universitatis Medicinalis Anhui 2016; 51(5): [13] de la Gala F, Piñeiro P, Garutti I, Reyes A, Olmedilla L, Cruz P, et al. Systemic and alveolar inflammatory response in the dependent and nondependent lung in patients undergoing lung resection surgery: A prospective observational study. Eur J Anaesthesiol 2015; 32(12): [14] Bastin AJ, Davies N, Lim E, Quinlan GJ, Griffiths MJ. Systemic inflammation and oxidative stress post-lung resection: Effect of pretreatment with N-acetylcysteine. Respirology 2016; 21(1): [15] Huang C, Pan L, Lin F, Dai H, Fu R. Monoclonal antibody against Toll-like receptor 4 attenuates ventilator-induced lung injury in rats by inhibiting MyD88- and NF-κB-dependent signaling. Int J Mol Med 2017; 39(3): [16] Musumeci G, Loreto C, Szychlinska MA, Imbesi R, Rapisarda V, Aiello FC, et al. N-Cadherin, ADAM-10 and Aquaporin 1 expression in lung tissue exposed to fluoro-edenite fibers: an immunohistochemical study. Histol Histopathol 2015; 30(8): [17] Gao S, Wang Y, Zhao J, Su A. Effects of dexmedetomidine pretreatment on heme oxygenase-1 expression and oxidative stress during one-lung ventilation. Int J Clin Exp Pathol 2015; 8(3): [18] Lin F, Pan LH, Ruan L, Qian W, Liang R, Ge WY, et al. Differential expression of HIF-1α, AQP-1, and VEGF under acute hypoxic conditions in the non-ventilated lung of a one-lung ventilation rat model. Life Sci 2015; 1(124):