Journal of Cancer Research and Therapeutics

ORIGINAL ARTICLE
Year
: 2018  |  Volume : 14  |  Issue : 7  |  Page : 1497--1502

Role of dexmedetomidine in reducing the incidence of postoperative cognitive dysfunction caused by sevoflurane inhalation anesthesia in elderly patients with esophageal carcinoma


He Zhang1, Zuoli Wu2, Xin Zhao1, Yong Qiao1,  
1 Department of Anesthesiology, The Second Affiliated Hospital of Shandong University, Jinan, Shandong, China
2 Department of Post Anesthesia Care Unit, Rizhao People's Hospital, Ji'ning Medical University, Rizhao, China

Correspondence Address:
Yong Qiao
Department of Anesthesiology, The Second Affiliated Hospital of Shandong University, Jinan 250033, Shandong
China

Abstract

Background: Sevoflurane anesthesia is a high-risk factor for postoperative cognitive dysfunction (POCD) in elderly patients. Recently, some studies demonstrated that dexmedetomidine (DEX) could reduce the incidence of POCD caused by sevoflurane anesthesia. We hypothesized that DEX could reduce the incidence of POCD caused by sevoflurane anesthesia through decreasing plasma interleukin (IL-6) and tumor necrosis factor (TNF)-α concentrations. Materials and Methods: A total of 120 patients aged 65–75 years scheduled for esophageal carcinoma resection were randomly assigned to four groups. Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were used to measure patients' cognitive function the day before operation and the 1st, 3rd, and 7th postoperative days. The plasma TNF-α, IL-6, and S100 β protein concentrations were measured by ELISA 10 min before anesthesia administration and the 1st, 3rd, and 7th postoperative days. Results: There were no significant differences in the demographic or clinical characteristics or perioperative hemodynamic status in all groups. Compared with Group M + P, the MMSE and MoCA scores were significantly lower and the plasma TNF-α, IL-6, and S100 β protein concentrations were significantly higher in Group M + S at the 1st, 3rd, and 7th postoperative days (P < 0.05). Compared with Group M + S, the MMSE and MoCA scores were significantly higher and the plasma TNF-α, IL-6, and S100 β protein concentrations were significantly lower in Group D + S at the 1st, 3rd, and 7th postoperative days (P < 0.05). Conclusion: The POCD incidence was higher in elderly patients receiving sevoflurane anesthesia and DEX could alleviate POCD in these patients through decreasing plasma TNF-α and IL-6 concentrations.



How to cite this article:
Zhang H, Wu Z, Zhao X, Qiao Y. Role of dexmedetomidine in reducing the incidence of postoperative cognitive dysfunction caused by sevoflurane inhalation anesthesia in elderly patients with esophageal carcinoma.J Can Res Ther 2018;14:1497-1502


How to cite this URL:
Zhang H, Wu Z, Zhao X, Qiao Y. Role of dexmedetomidine in reducing the incidence of postoperative cognitive dysfunction caused by sevoflurane inhalation anesthesia in elderly patients with esophageal carcinoma. J Can Res Ther [serial online] 2018 [cited 2020 Jan 20 ];14:1497-1502
Available from: http://www.cancerjournal.net/text.asp?2018/14/7/1497/247714


Full Text



 Introduction



Postoperative cognitive dysfunction (POCD) is characterized by progressive hypomnesia, personality change, or deterioration in cognitive function after surgery.[1] The incidence of POCD is rising steadily in patients receiving general anesthesia.[2],[3] Age is the main risk factor for POCD,[4] particularly those receiving sevoflurane anesthesia.[5] Central nervous system inflammation provoked by anesthesia plays an important role in POCD.[6] Anesthesia and surgery have been shown to increase the brain interleukin (IL)-6,[7] tumor necrosis factor (TNF)-α,[8] and S100 β protein.[8],[9] Dexmedetomidine (DEX) could significantly reduce inflammatory cell infiltration and cytokine release.[10] Some studies indicated that DEX could reduce POCD incidence, but the mechanism is not fully understood.

 Materials and Methods



The study was designed as a prospective, inpatient, double-blind, randomized, controlled trial. It was conducted at The Second Affiliated Hospital of Shandong University, obtaining approval from the local ethics committee and informed consent from each patient (trial registration: ChiCTR-IOR-15007007).

Patients

A total of 120 patients who underwent esophageal carcinoma between January 2013 and December 2015, aged between 65 and 75 years, were enrolled in this study. The patients were randomly assigned to the following four groups (n = 30): Group receiving midazolam and propofol anesthesia (Group M + P), group receiving midazolam and sevoflurane anesthesia (Group M + S), group receiving DEX and propofol anesthesia (Group D + P), and group receiving DEX and sevoflurane anesthesia (Group D + S).

The criteria for patients recruited in this study were as follows: (1) level of education that is capable of completing the neuropsychological tests; (2) preoperative Mini-Mental State Examination (MMSE) score ≥23; (3) no central nervous system lesions; (4) no taking tranquilizers or antidepressants; (5) no history of cardiovascular or respiratory disease; (6) no history of alcohol or cigarette abuse or drug dependence; (7) no obvious abnormal renal or hepatic functions; (8) no serious hearing or vision impairments; (9) no anaphylactic reactions to anesthetics.[11]

Patient management

Management of anesthesia followed standardized instructions, identical for each group. In the operation theater, the general hemodynamic parameters, including arterial blood pressure (BP), heart rate (HR), electrocardiography, blood oxygen saturation (SpO2), bispectral index (BIS), end-tidal partial pressure of carbon dioxide (PET CO2), and radial artery and internal jugular vein for monitoring the arterial BP and central venous pressure (CVP) were monitored after fasting for 8 h and abstinence from water for 4 h. All parameters were recorded at fixed intervals of 5 min.

Following a 3-min period of preoxygenation (100% O2), anesthesia was induced through a single slow intravenous injection of etomidate (0.3 mg/kg) and simultaneous infusion of sufentanil (0.4 μg/kg). Facilitation of tracheal intubation was achieved with cisatracurium besilate (0.3 mg/kg). Midazolam (2–3 mg) was injected in Group M + P and Group D + P. Patients in Group D + P and Group D + S received a loading dose of 1 μg/kg DEX, infused continuously for 12 min, and the loading dose was followed by a continuous intravenous infusion at a rate of 0.5 μg/kg/h. A double-lumen endobronchial tube of Robertshaw (diameter, 35–39 Fr) was placed in the left main bronchus through a laryngoscope.

The anesthesia machine parameters were set as follows: Tidal volume (VT = 7 ml/kg), respiratory rate (RR = 12 times/min), oxygen flow rate (2 L/min), positive end-expiratory pressure (PEEP = 5 cm H2O); I: E ratio of 1:2, and PET CO2 = 35–40 mmHg.

Maintenance of anesthesia was achieved by either propofol or sevoflurane. Group M + P and Group D + P was treated with propofol (4 ug/mL) by target-controlled infusion; Group M + S and Group D + S were treated with sevoflurane 1 minimum alveolar concentration (1 MAC). Infusion of remifentanil was carried out at a base rate of 0.15 μg/kg/h and titrated according to clinical needs. Cisatracurium besilate was administered at a short infusion of 5 mg/30 min according to clinical needs. Remifentanil infusion was increased based on hemodynamic change (HR and systolic arterial BP), BIS (50–60), and somatic (swallowing and movement) and autonomic signs (flushing, sweating, and salivating) until symptoms were resolved. Stop sevoflurane and propofol target-controlled infusion while starting the suture.

During the operation, to maintain a positive daily fluid balance and adequate urine output, all patients received normal saline infusion supplemented with lactated Ringer's solution (crystal, glue = 3:1) at an infusion rate of 0.5–1.0 mL/kg. min for 20–40 min, followed by an infusion rate of 0.25 mL/kg. min.

Postoperative analgesia was maintained by patient controlled intravenousanalgesia (PCIA) for 72 h with the following variables: 2-mL/h basal infusion, 0.5-mL patient-controlled bolus, and 15-min lockout.

All anesthesia-related data, including fluid input quantity, duration of operation, amount of bleeding, urine volume, time of single-lung ventilation, temperature, and time of spontaneous breathing recovery, eye opening after softly calling, and extubation after the surgery were recorded routinely. The indicators of intraoperative observation and record were as follows: HR, mean arterial pressure (MAP), and CVP at 5 time points, time of entering the operating room (T0), time before tracheal intubation (T1), time before operation (T2), time of the end of operation (T3), and time after tracheal extubation (T4).

Enzyme-linked immunosorbent assay

Blood was collected from the patients at different time points, 10 min before anesthesia (Ta) and the 1st (Tb), 3rd (Tc), and 7th (Td) days after operation, and plasma was prepared by centrifugation at 4000 ×g for 20 min at 4°C and stored at −80°C until use. IL-6, TNF-α, and S100 β protein concentrations were detected using an ELISA kit following the manufacturer's instructions and calculated using the standard curve provided with the kit.

Perioperative Cognitive Function Assessment

MMSE and Montreal cognitive assessment (MoCA) were used to assess the patients' cognitive function at the day before operation (Ts) and the 1st (Tb), 3rd (Tc), and 7th (Td) days after operation. The testers underwent a standard training and did not know the grouping of patients. MMSE is suitable for serious cognitive dysfunction, while MoCA is suitable for mild cognitive dysfunction. MMSE consists of orientation (orientation in time and place), memory (immediate and short-term memory), calculation, language (naming, repetition, listening and reading comprehension, and writing), visual-spatial ability, application, and attention. MoCA consists of the executive function of visual space (alternate trail making test, copy the cube, and clock drawing), language ability, attention and calculation, delayed recall, and abstract thinking. When the MMSE score ≥20, the patient's cognitive function was evaluated by MoCA.

Statistical analysis

Representative experiments from at least three independent experiments are shown. Statistical analysis was performed using the SPSS 19.0 for Windows (SPSS, IBM, USA). All data were expressed as means ± SDs. Significant differences were assessed using Student's t-tests or Tukey's test and Least significant difference with one-way analysis of variance (ANOVA), when appropriate. P 0.05 was considered statistically significant.

 Results



Participants' demographic and clinical characteristics

There were no significant differences between the groups in terms of sex, age, body mass index, or preoperative MMSE scores [Table 1], nor were there significant differences in perioperative hemodynamic parameters [Figure 1]a, [Figure 1]b, [Figure 1]c, time to recovery of spontaneous breathing, emergence from anesthesia, or time to extubation [Figure 1]d.{Table 1}{Figure 1}

Cognitive function assessment and plasma S100 β concentration

The MMSE and MoCA scores on the 1st, 3rd, and 7th postoperative days were significantly lower in Group M + S than Group M + P (P < 0.05); [Figure 2]a and [Figure 2]b. Furthermore, the MMSE and MoCA scores on the 1st, 3rd, and 7th postoperative days were significantly higher in Group D + S than Group M + S (P < 0.05); [Figure 2]a and [Figure 2]b. The plasma S100 β protein concentration was significantly higher in Group M + S than Group M + P and Group D + S at all postoperative time points (P < 0.05); [Figure 2]c. These findings suggest that sevoflurane inhalation anesthesia increases the incidence of POCD in elderly patients, as evidenced by increased plasma S100 β protein concentration and reduced MMSE and MoCA scores. DEX may be an effective means of reducing the incidence of POCD caused by sevoflurane inhalation anesthesia in elderly patients.{Figure 2}

Plasma interleukin-6 and tumor necrosis factor-α concentrations

The plasma IL-6 and TNF-α concentrations were significantly higher in Group M + S on the 1st, 3rd, and 7th postoperative days than Group M + P (P < 0.05); [Figure 3]a and [Figure 3]b and were significantly lower in Group M + S than Group D + S (P < 0.05); [Figure 3]a and [Figure 3]b at each time point. This suggests that sevoflurane anesthesia is associated with the release of IL-6 and TNF-α into the systemic circulation and that DEX may alleviate POCD caused by sevoflurane anesthesia by inhibiting their release.{Figure 3}

 Discussion



The aim of this study was to evaluate the effect of DEX in reducing POCD in elderly patients caused by sevoflurane inhalation anesthesia. Our finding implied a potential mechanism of POCD in elderly patients undergoing resection of esophageal carcinoma with sevoflurane inhalation anesthesia that may be involved in the release of plasma TNF-α and IL-6 during the surgical process.

POCD involves a wide range of cognitive functions including working memory, long-term memory, information processing, attention, and cognitive flexibility,[12] adversely affecting the quality of life, social dependence, and mortality.[13] The situation often occurs after the operation, continuing for weeks or months, existing for a long time in a few people.[14] In recent years, some studies found that sevoflurane inhalation anesthesia could cause the apoptosis of nerve cells, leading to the decline of the ability of learning and memory after anesthesia in animals.[15],[16],[17] Our study demonstrated that the cognitive function of patients treated with propofol was better than that of patients treated with sevoflurane and methylprednisolone could decrease the incidence of POCD by reducing the inflammatory reaction.[11],[18]

MMSE and MoCA were screening instruments to recognize cognitive dysfunction in elderly patients.[11] S100 β protein, which is an acidic calcium-binding protein, is a biomarker of central nervous system injury.[19] Increased S100 β protein concentration in the brain indicated severe brain injury.[20] S100 β protein concentration could reflect the incidence of POCD. Our results showed that MMSE and MoCA scores decreased and S100 β protein expression increased at the 1st, 3rd, and 7th days postoperatively in Group M + S compared with that in Group M + P. That is to say, elderly patients treated with sevoflurane inhalation anesthesia could have increased risk of POCD as noted in the decrease in MMSE and MoCA scores.

Injecting the neutralizing antibody of IL-6 could significantly improve the long-term potentiation (LTP) and spatial memory in rats. That indicated that IL-6 could affect the generation of LTP, inhibiting the ability of learning and memory and promoting the development of POCD.[21] Monocytes and macrophages were activated by external stimuli, releasing TNF-α, which was involved in inflammation, and also promoted the release of other inflammatory mediators such as IL-6, starting the inflammatory cascade reaction.[22] Isoflurane anesthesia could modulate the inflammatory factor TNF-α to develop POCD in diabetic rats.[23] Our study showed that sevoflurane inhalation anesthesia could lead to POCD, which was associated with IL-6 and TNF-α.[11] Our results showed that the plasma IL-6 and TNF-α concentrations increased at the 1st, 3rd, and 7th days after operation in Group M + S compared with that in Group M + P.

DEX could significantly reduce inflammatory cell infiltration and release of inflammatory cytokines.[24] DEX could alleviate the inflammatory action in rat sepsis model caused by LPS and enhance the livability of rat in infectious shock.[25] DEX could reduce the incidence of POCD, which might be related to the reduction of inflammatory factors. The study indicated that the plasma IL-6 and TNF-α concentrations in Group D + S at the 1st, 3rd, and 7th days after operation decreased compared with those in Group M + S. That indicated that the mechanism of POCD caused by sevoflurane inhalation anesthesia in elderly patients undergoing resection of esophageal carcinoma could be associated with pro-inflammatory factors IL-6 and TNF-α, which could be an important factor in the development of POCD. The increased plasma IL-6 and TNF-α concentrations could be the key role in POCD caused by sevoflurane inhalation anesthesia in elderly patients.

 Conclusion



In conclusion, POCD could be assessed with MMSE and MoCA scores and S100 β protein concentration. DEX could decrease the incidence of POCD caused by sevoflurane inhalation anesthesia associated with the decrease in plasma IL-6 and TNF-α concentrations.

Acknowledgments

The authors gratefully acknowledge the Medical Research Center of The Second Affiliated Hospital of Shandong University for equipment support and technical assistance. This work was supported by the Shandong Provincial Natural Science Foundation, China (ZR2013HL022), and Foundation of The Second Affiliated Hospital of Shandong University (Y2014010034).

Financial support and sponsorship

This work was financially supported by the Shandong Provincial Natural Science Foundation, China (ZR2013HL022), and Foundation of The Second Affiliated Hospital of Shandong University (Y2014010034).

Conflicts of interest

There are no conflicts of interest.

References

1Fong HK, Sands LP, Leung JM. The role of postoperative analgesia in delirium and cognitive decline in elderly patients: A systematic review. Anesth Analg 2006;102:1255-66.
2Rundshagen I. Postoperative cognitive dysfunction. Dtsch Arztebl Int 2014;111:119-25.
3Moller JT, Cluitmans P, Rasmussen LS, Houx P, Rasmussen H, Canet J, et al. Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International study of post-operative cognitive dysfunction. Lancet 1998;351:857-61.
4Monk TG, Weldon BC, Garvan CW, Dede DE, van der Aa MT, Heilman KM, et al. Predictors of cognitive dysfunction after major noncardiac surgery. Anesthesiology 2008;108:18-30.
5Rossi A, Burkhart C, Dell-Kuster S, Pollock BG, Strebel SP, Monsch AU, et al. Serum anticholinergic activity and postoperative cognitive dysfunction in elderly patients. Anesth Analg 2014;119:947-55.
6Lili X, Zhiyong H, Jianjun S. A preliminary study of the effects of ulinastatin on early postoperative cognition function in patients undergoing abdominal surgery. Neurosci Lett 2013;541:15-9.
7Li YC, Xi CH, An YF, Dong WH, Zhou M. Perioperative inflammatory response and protein S-100β concentrations – Relationship with post-operative cognitive dysfunction in elderly patients. Acta Anaesthesiol Scand 2012;56:595-600.
8Cao XZ, Ma H, Wang JK, Liu F, Wu BY, Tian AY, et al. Postoperative cognitive deficits and neuroinflammation in the hippocampus triggered by surgical trauma are exacerbated in aged rats. Prog Neuropsychopharmacol Biol Psychiatry 2010;34:1426-32.
9Benedict C, Cedernaes J, Giedraitis V, Nilsson EK, Hogenkamp PS, Vågesjö E, et al. Acute sleep deprivation increases serum levels of neuron-specific enolase (NSE) and S100 calcium binding protein B (S-100B) in healthy young men. Sleep 2014;37:195-8.
10Riker RR, Shehabi Y, Bokesch PM, Ceraso D, Wisemandle W, Koura F, et al. Dexmedetomidine vs. midazolam for sedation of critically ill patients: A randomized trial. JAMA 2009;301:489-99.
11Qiao Y, Feng H, Zhao T, Yan H, Zhang H, Zhao X, et al. Postoperative cognitive dysfunction after inhalational anesthesia in elderly patients undergoing major surgery: The influence of anesthetic technique, cerebral injury and systemic inflammation. BMC Anesthesiol 2015;15:154.
12Hovens IB, Schoemaker RG, van der Zee EA, Heineman E, Izaks GJ, van Leeuwen BL, et al. Thinking through postoperative cognitive dysfunction: How to bridge the gap between clinical and pre-clinical perspectives. Brain Behav Immun 2012;26:1169-79.
13Steinmetz J, Christensen KB, Lund T, Lohse N, Rasmussen LS; ISPOCD Group, et al. Long-term consequences of postoperative cognitive dysfunction. Anesthesiology 2009;110:548-55.
14Laalou FZ, Jochum D, Pain L. Postoperative cognitive dysfunction (POCD): Strategy of prevention, assessment and management. Ann Fr Anesth Reanim 2011;30:e49-53.
15Ikonomidou C, Bosch F, Miksa M, Bittigau P, Vöckler J, Dikranian K, et al. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 1999;283:70-4.
16Loepke AW, Istaphanous GK, McAuliffe JJ 3rd, Miles L, Hughes EA, McCann JC, et al. The effects of neonatal isoflurane exposure in mice on brain cell viability, adult behavior, learning, and memory. Anesth Analg 2009;108:90-104.
17Culley DJ, Loguinov A, Yukhananov R, Crosby G. General anesthesia does not reduce life expectancy in aged rats. Anesth Analg 2006;102:956-9.
18Rohan D, Buggy DJ, Crowley S, Ling FK, Gallagher H, Regan C, et al. Increased incidence of postoperative cognitive dysfunction 24 hr after minor surgery in the elderly. Can J Anaesth 2005;52:137-42.
19Herrmann M, Curio N, Jost S, Wunderlich MT, Synowitz H, Wallesch CW, et al. Protein S-100B and neuron specific enolase as early neurobiochemical markers of the severity of traumatic brain injury. Restor Neurol Neurosci 1999;14:109-14.
20Linstedt U, Meyer O, Kropp P, Berkau A, Tapp E, Zenz M, et al. Serum concentration of S-100 protein in assessment of cognitive dysfunction after general anesthesia in different types of surgery. Acta Anaesthesiol Scand 2002;46:384-9.
21Milligan ED, Sloane EM, Langer SJ, Cruz PE, Chacur M, Spataro L, et al. Controlling neuropathic pain by adeno-associated virus driven production of the anti-inflammatory cytokine, interleukin-10. Mol Pain 2005;1:9.
22Wu WC, Wang Y, Wang X, Rusidanmu A. Clinical analysis of acute lung injury after esophagectomy. J Cancer Res Ther 2014;10:314-8.
23Balschun D, Wetzel W, Del Rey A, Pitossi F, Schneider H, Zuschratter W, et al. Interleukin-6: A cytokine to forget. FASEB J 2004;18:1788-90.
24Yang L, Xu JM, Jiang X, Ruan W, Cui Y, He L, et al. Effect of dexmedetomidine on plasma brain-derived neurotrophic factor: A double-blind, randomized and placebo-controlled study. Ups J Med Sci 2013;118:235-9.
25Ji F, Li Z, Young N, Moore P, Liu H. Perioperative dexmedetomidine improves mortality in patients undergoing coronary artery bypass surgery. J Cardiothorac Vasc Anesth 2014;28:267-73.