Comparison of Different Doses of Amphotericin B Intrathecal Injection Combined with Continuous Cerebrospinal Fluid Drainage Replacement in the Treatment of Cryptococcal Meningitis
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摘要:
目的 探讨不同剂量两性霉素B鞘内注射治疗新型隐球菌性脑膜炎疗效与不良反应。 方法 按入组条件，收集2017年1月至2019年12月间，昆明市第三人民医院收治的新型隐球菌性脑膜炎病例，按入组标准选择69例，诱导治疗期在静脉注射两性霉素B及口服氟胞嘧啶的基础上，予以腰大池持续引流置换脑脊液，鞘内注射不同剂量的两性霉素B；随机分为4个组，A0、A1、A2每组17例，A3组18例。分别为A1（鞘内注射两性霉素B剂量0.2 mg）、A2（鞘内注射两性霉素B剂量0.3 mg）、A3（鞘内注射两性霉素B剂量0.5 mg）3组；A0为对照组（仅静脉注射两性霉素B及口服氟胞嘧啶，无鞘内注射给药）；观察治疗后1周、2周、4周，临床症状改善情况、脑脊液生化指标的变化，脑脊液中病原体的检测、影像学病灶的转归，以及不良反应。 结果 A1组不良反应的情况较A2、A3组少，差异有统计学意义（P < 0.001）；治疗4周后，A2、A3组脑脊液墨汁染色阳性率低于A1，差异有统计学意义（ P < 0.05）；A2、A3组脑脊液墨汁染色阳性率，差异无统计学意义（ P > 0.05）。磁共振显示A2组病灶明显吸收人数比率均高于A1、A3组，差异有统计学意义（ P < 0.05）；A1、A3组磁共振显示病灶明显吸收人数比率比较，差异无统计学意义（ P > 0.05）。A1组不良反应少，但疗效不及A2、A3组；A2组不良反应较A1组稍高、较A3组低，但A2组疗效最好；A3组因部分病例对不良反应难以耐受，不能每日进行鞘内注射，经治疗后从脑脊液蛋白及糖的恢复情况、影像学检查病灶吸收不及A2组。 结论 两性霉素B鞘内注射治疗隐球菌性脑膜炎时，若追求快速缓解病情而过快增加剂量，或长期使用较大剂量的两性霉素B鞘内注射带来的不良反应反而影响治疗的进度，干扰后期治疗效果，大部分患者更能接受低、中等剂量的两性霉素B鞘内注射。 Abstract:Objective To investigate the efficacy and side effects of different doses of amphotericin B intrathecal injection in the treatment of cryptococcal meningitis. Methods 69 cases of cryptococcal meningitis admitted in the Third People's Hospital of Kunming city from January 2017 to December 2019, were enrolled in this study. In the induction period, continuous drainage through the lumbar cisterm was performed to replace cerebrospinal fluid on the basis of intravenous amphotericin B and oral fluorocytosine, and different doses of amphotericin B were injected intrathecally. All the cases were randomly divided into 4 groups, 17 cases in A0, A1, A2 group respectively, 18 cases in A3 group. Experimental groups were A1（amphotericin intrathecal injection B dose 0.2 mg）, A2（amphotericin intrathecal injection B dose 0.3 mg）and A3（amphotericin intrathecal injection B dose 0.5 mg）. A0 was control group（intravenous amphotericin B and oral fluorocytosine only, no intrathecal injection）. Clinical symptoms, cerebrospinal fluid biochemical indicators, pathogens in CSF, imaging, and adverse reactions were observed at 1, 2, and 4 weeks after treatment. Results The adverse reactions in group A1 were significantly lower than those in group A2 and A3（P < 0.001）; After 4 weeks of treatment, the positive rate of CSF ink staining in A2 and A3 groups was significantly lower than that in A1 group（ P < 0.05）; The positive rate of cerebrospinal fluid ink staining in A2 and A3 groups has no statistic significance（ P > 0.05）. MRI showed that the ratio of obvious absorption of lesions in Group A2 was significantly higher than that in group A1 and Group A3（ P < 0.05）; Comparison of the ratio of obvious absorption of lesions in A1 and A3 groups by MRI showed no statistically significant difference（ P > 0.05）. There were fewer adverse reactions in group A1, but the efficacy was not as good as that in group A2 and A3; The adverse reactions in group A2 were slightly higher than that in group A1 and lower than that in group A3, but A2 has the best efficacy. Due to the intolerance of some patients to adverse reactions, the patients in A3 group could not receive intrathecal injection every day. After treatment, the recovery of cerebrospinal fluid protein and sugar and the absorption of lesions in imaging examination were not as good as those in A2 group. Conclusion When using amphotericin B intrathecal injection in treatment of cryptococcal meningitis, if the dosage was increased quickly in order for rapid improvement, or long-term use of large dose of amphotericin B intrathecal injection, the adverse reactions instead of improvement would bring negative effect on subsequent treatment. Most patients can tolerate lower, moderate dosage of amphotericin B intrathecal injection. -
表 1 各组间一般资料方差分析表（
$\bar x\pm s$ ）Table 1. Analysis of variance of general data among groups（
$\bar x \pm s$ ）分组 年龄（岁） F P A0 42.294 ± 9.544 A1 45.117 ± 16.458 0.56 0.64 A2 47.823 ± 12.192 A3 44.778 ± 10.553 
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表 2 鞘内注射组与对照组治疗4周后发热、头痛缓解的比例[n（%）]
Table 2. The proportion of fever and headache relief after 4 weeks of treatment between the intrathecal injection group and the control group[n（%）]
组别 发热 头痛 A0 3（17.6） 1（5.9） A1 10（58.8） 9（52.9） A2 16（94.1） 15（88.2） A3 10（55.6） 8（44.4） χ2 20.28 23.37 P < 0.001 < 0.001
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表 3 不同剂量鞘内注射组与对照组治疗4周后发热、头痛缓解两两比较
Table 3. Comparison of fever and headache relief after 4 weeks of treatment between different dosages of intrathecal injection group and control group
项目 发热 调整后α 头痛 χ2 P χ2 P A0与A1 6.10 0.013 0.008 9.07 0.003 A0与A2 20.16 < 0.001 0.008 23.14 < 0.001 A0与A3 5.38 0.020 0.008 6.81 0.009 A1与A2 5.88 0.039 0.008 5.10 0.024 A1与A3 0.04 0.845 0.008 0.25 0.620 A2与A3 6.81 0.009 0.008 7.44 0.006
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表 4 鞘内注射组与对照组治疗前与治疗4周格拉斯哥昏迷评分恢复情况对比[（
$ \bar x \pm s$ ），分]Table 4. Comparison of Glasgow coma score recovery before and 4 weeks after treatment between the intrathecal injection group and the control group[（
$ \bar x \pm s$ ），scores]临床表现 A0 A1 A2 A3 F P 入院 9.882 ± 3.37 9.647 ± 2.87 9.764 ± 2.31 9.778 ± 2.69 0.020 0.996 4周 11.351 ± 1.99 13.177 ± 1.74 14.529 ± 0.62 13.111 ± 1.75 11.001 < 0.001* t 21.888 22.594 24.133 24.502 P < 0.001 < 0.001 < 0.001 < 0.001
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表 5 治疗前后四组患者脑脊液白细胞变化情况比较[（
$ \bar x\pm s$ ），×106/L]Table 5. Comparison of the changes of cerebrospinal white blood cells in the four groups before and after treatment [（
$ \bar x\pm s$ ），×106/L]组别 治疗前 治疗1周 治疗2周 治疗4周 F分组 P分组 A0 85.58 ± 31.00 66.59 ± 29.42 50.82 ± 26.78 36.24 ± 19.74 A1 77.59 ± 30.31 60.76 ± 23.58 39.41 ± 19.31 24.71 ± 18.78 A2 77.78 ± 26.00 51.67 ± 22.09 30.22 ± 16.22 17.11 ± 10.82 3.12 0.03* A3 73.82 ± 20.94 54.12 ± 19.31 33.11 ± 20.89 18.76 ± 14.11 F时间 63 F时间×分组 0.34 P时间 < 0.001 P时间×分组 0.96 Mauchly’s球性检验λ = 0.62，χ2 = 30.42，P < 0.001，G-Ge = 0.78，H-Fe = 0.85。
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表 6 治疗前后四组患者脑脊液氯化物变化情况比较[（
$ \bar x\pm s$ ），mmol/L]Table 6. Comparison of CSF chloride changes before and after treatment among the four groups [（
$ \bar x\pm s$ ），mmol/L]组别 治疗前 治疗1周 治疗2周 治疗4周 F分组 P分组 A0 111.07 ± 5.50 115.10 ± 6.673 116.49 ± 6.37 119.41 ± 7.56 A1 107.73 ± 4.23 113.02 ± 4.47 117.411 ± 5.07 121.84 ± 6.99 A2 110.33 ± 5.55 115.95 ± 3.34 119.78 ± 3.86 123.31 ± 5.35 1.00 0.40 A3 107.84 ± 4.54 113.12 ± 4.21 118.67 ± 5.02 123.33 ± 5.59 F时间 86.42 F时间×分组 0.21 P时间 < 0.001 P时间×分组 0.11 Mauchly’s球性检验λ = 0.45，χ2= 50.48，P < 0.001，G-Ge = 0.66，H-Fe = 0.72。
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表 7 治疗前后四组患者脑脊液葡萄糖变化情况比较[（
$ \bar x \pm s $ ），mmol/L]Table 7. Comparison of cerebrospinal fluid（CSF）glucose changes in the four groups before and after treatment[（
$ \bar x \pm s $ ），mmol/L]组别 治疗前 治疗1周 治疗2周 治疗4周 F分组 P分组 A0 1.03 ± 0.49 1.35 ± 0.47 1.69 ± 0.35 1.93 ± 0.36 A1 1.11 ± 0.46 1.45 ± 0.54 1.84 ± 0.47 2.36 ± 0.44 A2 1.48 ± 0.69 1.67 ± 0.33 2.40 ± 0.33 2.96 ± 0.47 12.95 < 0.001 A3 1.32 ± 0.57 1.76 ± 0.64 2.45 ± 0.19 2.59 ± 0.78 F时间 55.19 F时间×分组 1.44 P时间 < 0.001 P时间×分组 0.17 Mauchly’s球性检验λ = 0.80，χ2= 13.25，P= 0.021，G-Ge = 0.89，H-Fe = 0.98。
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表 8 治疗前后四组患者脑脊液总蛋白变化情况比较[（
$ \bar x \pm s$ ），mg/L]Table 8. Comparison of changes in total cerebrospinal fluid protein between the four groups before and after treatment[（
$ \bar x \pm s$ ），mg/L]组别 治疗前 治疗1周 治疗2周 治疗4周 F分组 P分组 A0 820.47 ± 302.67 790.64 ± 343.34 811.82 ± 263.03 698.5.89 ± 262.18 A1 881.18 ± 243.35 735.24 ± 195.99 669.71 ± 171.56 494.22 ± 200.35 A2 893.24 ± 256.43 689.22 ± 167.06 522.35 ± 145.27 354.76 ± 147.35 2.46 0.07 A3 803.89 ± 203.29 703.00 ± 221.38 615.29 ± 144.27 445.35 ± 3167.5 F时间 47.93 F时间×分组 2.84 P时间 < 0.001 P时间×分组 0.004 Mauchly’s球性检验λ = 0.51，χ2= 42.39，P < 0.001，G-Ge = 0.68，H-Fe = 0.74。
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[1] 刘正印, 王贵强, 朱利平, 等. 隐球菌性脑膜炎诊治专家共识[J]. 中华内科杂志, 2018, 57（05）: 317-323. doi: 10.3760/cma.j.issn.0578-1426.2018.05.003 [2] 冉冬梅. 1000例真菌感染与耐药性分析[J]. 中国实用医药, 2016, 11（17）: 178-179. [3] 周亚彬, 王千, 张浩, 等. 国产两性霉素B及其他常用抗真菌药物对侵袭性真菌病病原菌的体外抑菌活性研究[J]. 中国真菌学杂志, 2018, 13（05）: 277-282. doi: 10.3969/j.issn.1673-3827.2018.05.005 [4] 何花, 黄瑛, 陈佳, 等. 脑脊液持续引流置换联合鞘内注射两性霉素B治疗新型隐球菌性脑膜炎临床分析[J]. 昆明医科大学学报, 2019, 40（02）: 110-115. doi: 10.3969/j.issn.1003-4706.2019.02.023 [5] 吕传真, 周良辅. 实用神经病学[M]. 上海: 上海科学技术出版社, 2016: 12. [6] 刘永权. 中国人隐球菌脑膜炎流行特征和CD44/脂筏-Src信号通路在新生隐球菌侵入人肺泡上皮细胞中的作用机制[D]. 广州: 南方医科大学硕士论文, 2015. [7] 李文风, 刘玥, 彭芸. 儿童隐球菌脑膜脑炎发病机制及CT、MRI表现研究进展[J]. 北京医学, 2018, 40（07）: 687-689. [8] 聂竞, 倪啸晓, 谢秋幼, 等. 意识障碍患者的临床并发症分析[J]. 临床神经外科杂志, 2020, 17（01）: 22-26+32. doi: 10.3969/j.issn.1672-7770.2020.01.006 [9] 向迅捷, 徐才邦, 孙力, 等. 脑室冲洗与常规脑脊液置换在脑脊液蛋白增高脑积水中的比较研究[J]. 国际神经病学神经外科学杂志, 2019, 46（06）: 650-653. [10] More A, Garg R K, Malhotra H S, et al. Acute vision loss in post-partum period as presenting symptom of HIV-associated cryptococcal meningitis-an unusual case report[J]. BMC Infect Dis, 2016, 16（1）: 582. doi: 10.1186/s12879-016-1925-0 [11] 李佳, 邓蓉, 刘焱斌. 两性霉素B治疗隐球菌脑膜炎的临床进展[J]. 临床误诊误治, 2019, 32（06）: 108-111. doi: 10.3969/j.issn.1002-3429.2019.06.026 [12] 李爱美, 李德帅. 8例隐球菌脑炎患者使用两性霉素B不良反应的观察及预防[J]. 现代医药卫生, 2009, 25（03）: 400-401, [13] 张昕, 涂波, 范荣, 等. 鞘内注射两性霉素B治疗隐球菌脑膜炎的META分析[J]. 中国真菌学杂志, 2012, 7（03）: 136-141, doi: 10.3969/j.issn.1673-3827.2012.03.003 [14] Yao Z, Liao W, Chen R. Management of cryptococcosis in non-HIV-related patients[J]. Med Mycol, 2005, 43（3）: 245-251, doi: 10.1080/13693780410001731628 [15] 王秋东. 两性霉素B静脉联合鞘内注射治疗新型隐球菌脑膜炎的疗效[J]. 中国实用神经疾病杂志, 2015, 18（06）: 111-112, doi: 10.3969/j.issn.1673-5110.2015.06.071 [16] 成钢卫, 李水彬, 罗丽敏, 等. 两性霉素脂质体鞘内注射治疗新型隐球菌性脑膜炎疗效观察[J]中国医院用药评价与分析. 2008. 8（5）: 382-383, doi: 10.3969/j.issn.1672-2124.2008.05.025 [17] 周兆珍, 邢春礼, 李修敏. 超长疗程鞘内注射两性霉素B治疗SLE并隐球菌脑膜炎1例[J]. 中国医药指南, 2016, 14（31）: 207-208, -
