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中华口腔医学研究杂志(电子版)

中华口腔医学研究杂志(电子版) ›› 2019, Vol. 13 ›› Issue (03) : 166 -173. doi: 10.3877/cma.j.issn.1674-1366.2019.03.006

所属专题： 文献；

临床研究

口腔颌面部手术术后谵妄危险因素的Meta分析
余晓宁1, 蔡洁琛2, 黄利浩2, 竺越3, 侯劲松3,†()   
  1. 1. 中山大学光华口腔医学院·附属口腔医院，广东省口腔医学重点实验室，广州　510055；惠州市第一人民医院口腔科　516003
    2. 惠州市第一人民医院口腔科　516003
    3. 中山大学光华口腔医学院·附属口腔医院，广东省口腔医学重点实验室，广州　510055
  • 收稿日期:2019-03-20 出版日期:2019-06-01
  • 通信作者: 侯劲松

Risk factors for postoperative delirium after oral and maxillofacial surgery: a Meta-analysis

Xiaoning Yu1, Jiechen Cai2, Lihao Huang2, Yue Zhu3, Jinsong Hou3,†()   

  1. 1. Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, China; Department of Stomatology, Huizhou First Peoples Hospital, Huizhou 516003, China
    2. Department of Stomatology, Huizhou First Peoples Hospital, Huizhou 516003, China
    3. Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, China
  • Received:2019-03-20 Published:2019-06-01
  • Corresponding author: Jinsong Hou
  • About author:
    Corresponding author: Hou Jinsong, Email:
  • Supported by:
    Science and Technology Major Project of Huizhou City(2018Y084)
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引用本文：

余晓宁, 蔡洁琛, 黄利浩, 竺越, 侯劲松. 口腔颌面部手术术后谵妄危险因素的Meta分析[J]. 中华口腔医学研究杂志(电子版), 2019, 13(03): 166-173.

Xiaoning Yu, Jiechen Cai, Lihao Huang, Yue Zhu, Jinsong Hou. Risk factors for postoperative delirium after oral and maxillofacial surgery: a Meta-analysis[J]. Chinese Journal of Stomatological Research(Electronic Edition), 2019, 13(03): 166-173.

目的

分析口腔颌面部手术术后谵妄（POD）的相关危险因素，为临床有效预防POD提供依据。

方法

检索Web of Science、PubMed、Cochrane Library、EMbase数据库，时间为数据库建库至2018年7月1日，查找关于口腔颌面部手术POD的相关文献，按照纳入、排除标准进行筛选，对纳入的文献进行质量评估，提取关于POD相关因素的数据，采用RevMan 5.3、StataSE 12.0软件进行统计学分析。

结果

共纳入11篇口腔颌面部手术POD的相关研究，涉及口腔颌面部手术2429例患者，其中发生POD共415例（发生率17.1%）。研究结果显示，年龄、男性、独居、精神状态、高血压、术前血红蛋白、总蛋白、术中麻醉时间、手术时间、失血量、气管切开术、术后疼痛为口腔颌面部手术POD的危险因素（P<0.05），而吸烟、酗酒、美国麻醉医师学会（ASA）分级、糖尿病、心脏病、术前血清钠、术前白蛋白、输液量、颈淋巴清扫术、皮瓣转移修复术与POD无明显相关性（P>0.05）。

结论

临床上口腔颌面外科医生在术前应密切关注患者的年龄、性别、精神状态、高血压及相关实验室结果（术前血红蛋白、总蛋白）；术中应密切控制麻醉时间和手术时间，减少出血，维持良好通气；术后做好镇痛管理，能有效预防POD发生。

关键词: 口腔颌面部, 手术，口腔, 谵妄，手术后
Objective

In order to provide evidence for the effective clinical prevention of postoperative delirium (POD) , this study analyzed the related risk factors of POD after oral and maxillofacial surgery.

Methods

Databases including Web of Science, PubMed, Cochrane Library and EMbase were included in the searching of literatures about delirium after oral and maxillofacial surgery. The searching period was from the establishment of the databases to July 1st, 2018. The literatures were screened strictly according to the included and excluded criteria, and their quality was evaluated afterwards. POD′s related factors were extracted as available data. Statistical analysis was carried out by using RevMan 5.3 and StataSE 12.0.

Results

In total, 11 original studies with 2429 patients were included, in which 415 patients (17.1%) suffered from POD. The results showed that age, gender, solitary life, mental status, history of hypertension, preoperative hemoglobin and total protein, intraoperative anesthesia time, operation time, blood loss, tracheotomy, postoperative pain were risk factors for delirium after oral and maxillofacial surgery (P<0.05) , while smoking, alcoholism, ASA scale, diabetes mellitus, heart disease, preoperative serum sodium, preoperative albumin, infusion volume, neck dissection, free flap transfer were not significantly correlated (P>0.05) .

Conclusions

Patients′ age, gender, mental status, hypertension and related laboratory results (preoperative hemoglobin, total protein) should be paid close attention before oral and maxillofacial surgery. Factors including anesthesia time, operation time, bleeding and ventilation should be strictly controlled. Besides, postoperative analgesia should be well managed since it can effectively prevent POD.

Key words: Oral and maxillofacial, Surgery, oral, Delirium, postoperative
表1 纳入口腔颌面部手术术后谵妄相关危险因素研究文献的一般特征
纳入文献 诊断方法 谵妄/非谵妄 研究设计 质量评估（分） 影响因素
Booka 2016[8] DSM-Ⅴ 50/243 回顾性研究 8 年龄、男性、吸烟、饮酒、精神状态、ASA分级、心脏病、高血压、糖尿病、输液量、手术时间、失血量、皮瓣转移修复术、气管切开
Choi 2017[9] DSM-Ⅳ 89/252 回顾性研究 9 年龄、精神状态、ASA分级、麻醉时间、气管切开、睡眠障碍、术前血清钠、术前白蛋白
Hasegawa 2015[10] DSM-Ⅳ 29/159 队列研究 8 年龄、男性、吸烟、饮酒、精神状态、心脏病、高血压、糖尿病、住院天数、手术时间、失血量、颈淋巴清扫术、气管切开、术前血清钠、术前血红蛋白、术前白蛋白、术前总蛋白
Kinugawa 2018[11] 临床诊断 6/40 回顾性研究 8 年龄、男性、精神状态、高血压、住院天数、麻醉时间、手术时间、失血量、术前血红蛋白、术前总蛋白
Kunimatsu 2004[12] ICD-10 13/23 回顾性研究 8 年龄、男性、ASA分级、麻醉时间、手术时间
Makiguchi 2018[13] DSM-Ⅳ 34/68 队列研究 7 年龄、男性、吸烟、饮酒、精神状态、ASA分级、糖尿病、输液量、手术时间、失血量、睡眠障碍、术前血红蛋白、术前白蛋白、术前总蛋白
Shah 2012[14] 临床诊断 89/685 队列研究 8 男性、独居、饮酒、精神状态
Shiiba 2009[15] DSM-Ⅳ 24/108 回顾性研究 7 年龄、男性、麻醉时间、输液量、手术时间、失血量、皮瓣转移修复术、气管切开、疼痛、术前血清钠、术前血红蛋白、术前白蛋白、术前总蛋白
Wang 2004[16] DSM-Ⅲ 47/294 回顾性研究 8 年龄、男性、颈淋巴清扫术、皮瓣转移修复术
Weed 1995[17] MMSE 24/114 队列研究 7 年龄、男性、独居、饮酒、精神状态、心脏病、ASA分级、住院时间、麻醉时间、颈淋巴清扫术、皮瓣转移修复术
Yamagata 2005[18] 临床诊断 10/28 回顾性研究 7 年龄、男性、独居、吸烟、饮酒、精神状态、ASA分级、输液量、手术时间、颈淋巴清扫术、皮瓣转移修复术、气管切开、疼痛
表2 口腔颌面部手术术后谵妄各影响因素Meta分析结果
因素 文献数 病例数 谵妄人数 统计学方法 OR或MD［95% CI］ 异质性I2（%） P值
年龄 10 1655 326 Ⅳ.random 5.61［3.11，8.10］ 85 <0.0001
年龄>70岁 3 772 121 M-H.fixed 2.60［1.71，3.97］ 33 <0.0001
男性 10 2088 326 M-H.fixed 1.79［1.35，2.38］ 46 <0.0001
独居 3 950 123 M-H.fixed 1.60［1.03，2.47］ 60 0.03
吸烟 4 621 123 M-H.fixed 1.19［0.78，1.82］ 27 0.42
酗酒 6 1533 236 M-H.fixed 1.05［0.79，1.39］ 54 0.76
精神状态 8 1920 331 M-H.random 2.97［1.45，6.79］ 61 0.003
ASA分级 5 810 196 Ⅳ.random 0.16［-0.01，0.34］ 73 0.06
高血压 3 527 85 M-H.fixed 1.93［1.17，3.18］ 0 0.01
糖尿病 3 583 113 M-H.random 2.45［0.50，12.12］ 86 0.27
心脏病 3 619 103 M-H.fixed 0.95［0.47，1.93］ 30 0.89
麻醉时间 5 693 156 Ⅳ.random 65.89［18.19，113.59］ 75 0.007
输液量 4 565 118 Ⅳ.fixed 178.80［-46.68，404.27］ 0 0.12
手术时间 7 835 166 Ⅳ.random 82.53［36.50，128.56］ 67 0.0004
失血量 5 761 143 Ⅳ.fixed 61.23［19.88，102.59］ 48 0.004
颈淋巴清扫术 4 705 110 M-H.fixed 1.29［0.85，1.96］ 61 0.23
皮瓣转移修复术 4 810 131 M-H.fixed 1.53［0.98，2.37］ 39 0.06
气管切开术 5 992 202 M-H.fixed 1.89［1.35，2.66］ 0 0.0002
睡眠障碍 2 443 123 M-H.random 4.98［1.36，18.27］ 76 0.02
疼痛 2 170 34 M-H.fixed 2.91［1.23，6.92］ 0 0.02
住院天数 3 372 59 Ⅳ.random 7.58［2.00，13.16］ 71 8
术前血清钠 3 661 142 Ⅳ.fixed 0.15［-0.37，0.66］ 20 0.58
术前血红蛋白 4 468 93 Ⅳ.random -2.27［-7.17，2.63］ 67 0.36
术前白蛋白 4 763 176 Ⅳ.random -0.53［-3.22，2.17］ 89 0.7
术前总蛋白 4 468 93 Ⅳ.random -1.29［-5.01，2.42］ 87 0.5
表3 口腔颌面部手术术后谵妄危险因素的敏感性分析及Egger检验结果
因素 Galbraithe图提示存在异质性的研究 排除异质性研究后统计合并效应 P值 Egger检验
OR或MD［95% CI］ 异质性I2（%）
年龄 Choi 2017 3.18［1.95，4.41］ 77 <0.0001 0.068
Hasegawa 2015 ? ? ? ?
Kinugawa 2018 ? ? ? ?
独居 n.s. 1.60［1.03，2.47］ 60 0.03 0.611
酗酒 n.s. 1.05［0.79，1.39］ 54 0.76 0.751
精神状态 Hasegawa 2015 2.91［1.84，4.58］ 40 <0.0001 0.272
Kinugawa 2018 ? ? ? ?
ASA分级 Booka 2016 0.08［-0.06，0.22］ 45 0.24 0.486
糖尿病 Makiguchi 2018 1.23［0.45，3.35］ 38 0.69 0.699
麻醉时间 Kinugawa 2018 45.76［20.80，70.73］ 31 0.0003 0.09
手术时间 Kinugawa 2018 51.45［10.77，94.14］ 37 0.01 0.918
Yamagata 2005 ? ? ? ?
颈淋巴清扫术 n.s. 1.29［0.85，1.96］ 61 0.23 0.947
住院天数 Hasegawa 2015 n.s. n.s. n.s. n.s.
Weed 1995 ? ? ? ?
术后睡眠障碍 n.s. 4.98［1.36，18.27］ 76 0.02 n.s.
术前血红蛋白 Makiguchi 2018 -4.70［-7.67，-1.73］ 0 0.002 0.366
术前白蛋白 Hasegawa 2015 -1.04［-2.13，0.05］ 0 0.06 0.778
Makiguchi 2018 ? ? ? ?
术前总蛋白 Hasegawa 2015 -2.42［-4.39，-0.45］ 0 0.02 0.653
Makiguchi 2018 ? ? ? ?
[1]
Setters B, Solberg LM. Delirium[J]. Prim Care, 2017, 44(3): 541-559. DOI: 10.1016/j.pop.2017.04.010.
[2]
Regal PJ. Delirium, in 405 articles of medical（non-surgical or ICU）inpatients: unproven speed of onset and recovery[J]. Clin Interv Aging, 2017(12): 377-380. DOI: 10.2147/CIA.S129255.
[3]
Kim S, Kim JJ, Oh J, et al. Delirium characteristics and outcomes in medical and surgical lnpatients: A subgroup analysis[J]. J Crit Care, 2018(43): 156-162. DOI: 10.1016/j.jcrc.2017.08.011.
[4]
Cavaliere F, D′ambrosio F, Volpe C, et al. Postoperative delirium[J]. Curr Drug Targets, 2005, 6(7): 807-814. DOI: 10.2174/138945005774574489.
[5]
Moskowitz EE, Overbey DM, Jones TS, et al. Post-operative delirium is associated with increased 5-year mortality[J]. Am J Surg, 2017, 214(6): 1036-1038. DOI: 10.1016/j.amjsurg.2017.08.034.
[6]
Bhat RS, Rockwood K. The role of diagnosis in delirium[J]. Int Psychogeriatr, 2016, 28(10): 1579-1586. DOI: 10.1017/s1041610216001095.
[7]
Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses[J]. Eur J Epidemiol, 2010, 25(9): 603-605. DOI: 10.1007/s10654-010-9491-z.
[8]
Booka E, Kamijo T, Matsumoto T, et al. Incidence and risk factors for postoperative delirium after major head and neck cancer surgery[J]. J Craniomaxillofac Surg, 2016, 44(7): 890-894. DOI: 10.1016/j.jcms.2016.04.032.
[9]
Choi NY, Kim EH, Baek CH, et al. Development of a nomogram for predicting the probability of postoperative delirium in patients undergoing free flap reconstruction for head and neck cancer[J]. Eur J Surg Oncol, 2017, 43(4): 683-688. DOI: 10.1016/j.ejso.2016.09.018.
[10]
Hasegawa T, Saito I, Takeda D, et al. Risk factors associated with postoperative delirium after surgery for oral cancer[J]. J Craniomaxillofac Surg, 2015, 43(7): 1094-1098. DOI: 10.1016/j.jcms.2015.06.011.
[11]
Kinugawa T, Morimoto Y, Hayashi M, et al. Risk factors for postoperative delirium in elderly patients undergoing non-major oral and maxillofacial surgery-a retrospective chart study[J]. Biomedical Research（India）, 2018, 29(2): 227-233. DOI: 10.4066/biomedicalresearch.29-17-2025.
[12]
Kunimatsu T, Misaki T, Hirose N, et al. Postoperative mental disorder following prolonged oral surgery[J]. J Oral Sci, 2004, 46(2): 71-74. DOI: 10.2334/josnusd.46.71.
[13]
Makiguchi T, Yokoo S, Kurihara J. Risk factors for postoperative delirium in patients undergoing free flap reconstruction for oral cancer[J]. Int J Oral Maxillofac Surg, 2018, 47(8): 998-1002. DOI: 10.1016/j.ijom.2018.03.011.
[14]
Shah S, Weed HG, He X, et al. Alcohol-related predictors of delirium after major head and neck cancer surgery[J]. Arch Otolaryngol Head Neck Surg, 2012, 138(3): 266-71. DOI: 10.1001/archoto.2011.1456.
[15]
Shiiba M, Takei M, Nakatsuru M, et al. Clinical observations of postoperative delirium after surgery for oral carcinoma[J]. Int J Oral Maxillofac Surg, 2009, 38(6): 661-665. DOI: 10.1016/j.ijom.2009.01.011.
[16]
Wang SG, Lee BJ, Goh EK, et al. Factors associated with postoperative delirium after major head and neck surgery[J]. Ann Otol Rhinol Laryngol, 2004, 113(1): 48-51. DOI: 10.1177/000348940411300111.
[17]
Weed HG, Lutman CV, Young DC, et al. Preoperative identification of patients at risk for delirium after major head and neck cancer surgery[J]. Laryngoscope, 1995, 105(10): 1066-1068. DOI: 10.1288/00005537-199510000-00011.
[18]
Yamagata K, Onizawa K, Yusa H, et al. Risk factors for postoperative delirium in patients undergoing head and neck cancer surgery[J]. Int J Oral Maxillofac Surg, 2005, 34(1): 33-36. DOI: 10.1016/j.ijom.2004.03.005.
[19]
Donald A, Goldmann MD. The American Society of Anesthesiologists Physical Status Score and Risk of Perioperative Infection-Reply[J]. JAMA, 1996, 275(20): 1544. DOI: 10.1001/jama.1996.03530440022022.
[20]
Watt J, Tricco AC, Talbot-Hamon C, et al. Identifying Older Adults at Risk of Delirium Following Elective Surgery: A Systematic Review and Meta-Analysis[J]. J Gen Intern Med, 2018, 33(4): 500-509. DOI: 10.1007/s11606-017-4204-x.
[21]
Davis D, Richardson S, Hornby J, et al. The delirium and population health informatics cohort study protocol: ascertaining the determinants and outcomes from delirium in a whole population[J]. BMC Geriatr, 2018, 18(1): 45. DOI: 10.1186/s12877-018-0742-2.
[22]
Dilger RN, Johnson RW. Aging, microglial cell priming, and the discordant central nflammatory response to signals from the peripheral immune system[J]. J Leukoc Biol, 2008, 84(4): 932-939. DOI: 10.1189/jlb.0208108.
[23]
Van Eijk LT, Dorresteijn MJ, Smits P, et al. Gender differences in the innate immune response and vascular reactivity following the administration of endotoxin to human volunteers[J]. Crit Care Med, 2007, 35(6): 1464-1469. DOI: 10.1097/01.ccm.0000266534.14262.e8.
[24]
Heinrich LM, Gullone E. The clinical significance of loneliness: a literature review[J]. Clin Psychol Rev, 2006, 26(6): 695-718. DOI: 10.1016/j.cpr.2006.04.002.
[25]
Smith PJ, Attix DK, Weldon BC, et al. Depressive Symptoms and Risk of Postoperative Delirium[J]. Am J Geriatr Psychiatry, 2016, 24(3): 232-238. DOI: 10.1016/j.jagp.2015.12.004.
[26]
Wada S, Inoguchi H, Sadahiro R, et al. Preoperative Anxiety as a Predictor of Delirium in Cancer Patients: A Prospective Observational Cohort Study[J]. World J Surg, 2019, 43(1): 134-142. DOI: 10.1007/s00268-018-4761-0.
[27]
Li H, Sagar AP, Kéri S. Microglial markers in the frontal cortex are related to cognitive dysfunctions in major depressive disorder[J]. J Affect Disord, 2018(241): 305-310. DOI: 10.1016/j.jad.2018.08.021.
[28]
Stein DJ, Aguilar-Gaxiola S, Alonso J, et al. Associations between mental disorders and subsequent onset of hypertension[J]. Gen Hosp Psychiatry, 2014, 36(2): 142-149. DOI: 10.1016/j.genhosppsych.2013.11.002.
[29]
Korte SM, Koolhaas JM, Wingfield JC, et al. The Darwinian concept of stress: benefits of allostasis and costs of allostatic load and the trade-offs in health and disease[J]. Neurosci Biobehav Rev, 2005, 29(1): 3-38. DOI: 10.1016/j.neubiorev.2004.08.009.
[30]
Zhang Y, Li HJ, Wang DX, et al. Impact of inhalational versus intravenous anaesthesia on early delirium and long-term survival in elderly patients after cancer surgery: study protocol of a multicentre, open-label, and randomised controlled trial[J]. BMJ Open, 2017, 7(11): e018607. DOI: 10.1136/bmjopen-2017-018607.
[31]
Maclullich AM, Ferguson KJ, Miller T, et al. Unravelling the pathophysiology of delirium: a focus on the role of aberrant stress responses[J]. J Psychosom Res, 2008, 65(3): 229-238. DOI: 10.1016/j.jpsychores.2008.05.019.
[32]
Mutch WAC, El-Gabalawy R. Anesthesia and postoperative delirium: the agent is a strawman - the problem is CO2[J]. Can J Anaesth, 2017, 64(6): 678-680. DOI: 10.1007/s12630-017-0859-3.
[33]
González-López A, Albaiceta GM, Talbot K. Newly identified precipitating factors in mechanical ventilation-induced brain damage: implications for treating ICU delirium[J]. Expert Rev Neurother, 2014, 14(6): 583-588. DOI: 10.1586/14737175.2014.915743.
[34]
Mansour AR, Farmer MA, Baliki MN, et al. Chronic pain: the role of learning and brain plasticity[J]. Restor Neurol Neurosci, 2014, 32(1): 129-139. DOI: 10.3233/RNN-139003.
[35]
Hessler JB, Brönner M, Etgen T, et al. Smoking increases the risk of delirium for older inpatients: a prospective population-based study[J]. Gen Hosp Psychiatry, 2015, 37(4): 360-364. DOI: 10.1016/j.genhosppsych.2015.03.009.
[36]
Wansrisuthon W, Ratta-Apha W, Thongchot L, et al. Accuracy of Diagnosis and International Classification of Diseases；Tenth Revision Coding for Alcohol Dependence, Alcohol Withdrawal, and Alcohol-withdrawal Delirium Among Inpatients at a University Hospital[J]. J Addict Med, 2017, 11(3): 241-242. DOI: 10.1097/adm.0000000000000307.
[37]
Al-Atram AA. A review of the bidirectional relationship between psychiatric disorders and diabetes mellitus[J]. Neurosciences （Riyadh）, 2018, 23(2): 91-96. DOI: 10.17712/nsj.2018.2.20170132.
[38]
Kumar P, Raman T, Swain MM, et al. Hyperglycemia-Induced Oxidative-Nitrosative Stress Induces Inflammation and Neurodegeneration via Augmented Tuberous Sclerosis Complex-2（TSC-2）Activation in Neuronal Cells[J]. Mol Neurobiol, 2017, 54(1): 238-254. DOI: 10.1007/s12035-015-9667-3.
[39]
Dadu RT, Fornage M, Virani SS, et al. Cardiovascular biomarkers and subclinical brain disease in the atherosclerosis risk in communities study[J]. Stroke, 2013, 44(7): 1803-1808. DOI: 10.1161/STROKEAHA.113.001128.
[40]
Oliveira FR, Oliveira VH, Oliveira ÍM, et al. Hypertension, mitral valve disease, atrial fibrillation and low education level predict delirium and worst outcome after cardiac surgery in older adults[J]. BMC Anesthesiol, 2018, 18(1): 15. DOI: 10.1186/s12871-018-0481-0.
[41]
Grotti S, Falsini G. Delirium in cardiac patients[J]. Eur Heart J, 2017, 38(29): 2244. DOI: 10.1093/eurheartj/ehx380.
[42]
Sanford AM, Flaherty JH. Do nutrients play a role in delirium？[J]. Curr Opin Clin Nutr Metab Care, 2014, 17(1): 45-50. DOI: 10.1097/mco.0000000000000022.
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