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Serum Uric Acid Levels in Chinese Patients with Classic Multiple Sclerosis: Before and After Treatment with Interferon-beta 1b
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摘要:目的 探讨中国经典型多发性硬化(classical multiple sclerosis, CMS)患者β干扰素-1b治疗前后血清尿酸(uric acid, UA)水平的变化及其与复发率、扩展残疾状态评分(Expanded Disability Status Scale, EDSS)和颅内增强病灶(contrast-enhancing lesions, CELs)数目间的关系。方法 12例CMS患者(10例女性, 2例男性, 年龄:24~54岁)被纳入至一项为期6个月的疗效观察研究。在疾病缓解期, 给予β干扰素-1b(250 μg, 皮下注射, 隔日1次)治疗。治疗前后评估患者EDSS评分、年复发次数、颅内CELs数目和血清UA水平。结果 治疗后, 患者年复发次数(0.0比0.9, P=0.011)和颅内CELs数目(0.0比1.5, P=0.007)较治疗前明显减低; EDSS评分有降低趋势(2.0比2.8), 但差异无统计学意义(P=0.064);血清UA水平从222.2 μmol/L升高至234.9 μmol/L, 但差异亦无统计学意义(P=0.213)。进一步研究发现, 血清UA水平升高与颅内CELs数目减低显著相关(r=-0.716, P=0.009)。结论 血清UA水平有可能成为评估CMS患者对β干扰素-1b治疗反应的一个监测指标。Abstract:Objective To investigate the changes of serum uric acid (UA) level and its relationship with relapse rate, Expanded Disability Status Scale (EDSS) score, and the number of contrast-enhancing lesions (CELs) in Chinese patients with classic multiple sclerosis (CMS) before and after interferon (IFN) -beta 1b treatment.Methods Twelve patients (10 women and 2 men, aged 24 to 54 years) with definite CMS were enrolled into a 6-month open-label observational treatment study. IFN-beta 1b (250 μg, qod) was injected subcutaneously during remission stage. EDSS, relapse rate, number of CELs, and serum UA levels were examined both at baseline and at the end of the study.Results After treatment, the median relapse rate (0.0 vs. 0.9, P=0.011) and median number of CELs (0.0 vs. 1.5, P=0.007) decreased significantly compared with those before treatment. The median EDSS score also decreased from 2.8 to 2.0, but the difference was not statistically significant (P=0.064). Serum UA level increased from 222.2 μmol/L to 239.4 μmol/L after treatment, although the difference was not statistically significant (P=0.213). However, there was significant correlation between the increase in UA level and the decrease in number of CELs (r=-0.716, P=0.009).Conclusions UA may serve as an easily detectable and economic marker for the blood-brain barrier function in CMS patients and for the responses to IFN-beta 1b treatment.
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Keywords:
- multiple sclerosis /
- uric acid /
- interferon-beta
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Shikani可视插管镜(视可尼可视光学导芯，Shikani optical stylet/seeing optical stylet，SOS)是可视硬质管芯类无创困难气道工具的代表之一，于1996年通过美国食品和药物管理局(Food and Drug Administration，FDA)批准并应用于临床气道管理[1]，尤其适用于困难气道的气管插管，如张口度受限、颈椎活动度受限、Cormack分级高的患者。本研究将Shikani可视插管镜与Macintosh喉镜用于非困难气道患者，比较两种喉镜的插管反应和插管并发症，评价Shikani可视插管镜的临床应用价值和前景。
对象和方法
对象
本研究共纳入2010年10月至2011年5月40例拟在气管插管全身麻醉下接受妇科腹腔镜或开腹手术的女性患者。研究开始前获得本院伦理委员会批准，试验开始前与患者签署知情同意书。纳入标准:美国麻醉医师协会(American Society of Anesthesiologists，ASA)分级Ⅰ级，术前气道评估排除困难气道(Mallampati分级Ⅰ或Ⅱ级，上下门齿间距＞3 cm，甲颏距＞6 cm，头后仰不受限)，无高血压、心动过速或心动过缓、心律失常。排除标准:合并循环系统疾病，术前评估疑为困难气道，拒绝签署知情同意书。
根据随机表将40例患者随机分成两组，分别为Macintosh喉镜组(D组)，20例; Shikani可视插管镜组(L组)，20例。
麻醉方法
所有患者均采用静脉快速诱导气管内插管全身麻醉。患者入室后即建立20G静脉通路，立即快速输注乳酸钠林格500 ml进行容量补充。监测无创血压(noninvasive blood pressure，NBP)、心电图(electrocardiogram，ECG)、脉搏氧饱和度(oxygen saturation by pulse oximetry，SpO2)。经静脉给予咪达唑仑40 μg/kg、芬太尼2 μg/kg、昂丹司琼4 mg，随即开始为患者吸氧去氮，5 min后开始用GRASBY3500靶控注射泵靶控输注丙泊酚，初始靶浓度为6 μg/ml，待患者意识消失后给予罗库溴铵0. 6 mg/kg，1 min后进行气管插管。各组气管插管操作均由同一位有经验的麻醉医师完成。另一位麻醉医师于插管前后分别测量并记录患者的平均动脉压、心率以及气管导管误入食道的次数和从插管工具置入患者口中至气管插管到位所需时间。插管完成后听诊双侧呼吸音，确认导管位置适合后，固定导管并开始机械通气。
麻醉维持采用1:1氧气和笑气，丙泊酚靶浓度为3. 0 ~ 4. 0 μg/ml，根据需要间断追加芬太尼和罗库溴铵。术毕停止丙泊酚，唤醒患者送至恢复室，待患者完全清醒符合离开恢复室标准后记录其咽痛、声嘶主诉。
插管方法
D组行常规Macintosh喉镜插管。患者头部取嗅物位，将3号Macintosh镜片从右侧口角置入患者口中，逐渐深入，依次观察到悬雍垂、会厌、声门，将导管送入气管内。
L组应用Shikani可视插管镜。预先将气管导管套在Shikani可视插管镜上，导芯尖端不超过气管导管的开口，以免造成组织损伤或分泌物模糊视野。将室内光线调暗，提起患者下颌，从左侧口角置入Shikani可视插管镜，注意观察患者颈部甲状软骨后方的光斑，继续推进Shikani可视插管镜，直至观察到光斑由弥散的圆形逐渐聚拢成线形并向胸骨上窝方向放射，此时表明气管导管尖端已进入声门，经目镜可窥见气管软骨环，一手固定Shikani可视插管镜，另一手将导管送入气管内。
统计学处理
应用SPSS 17. 0和Microsoft Office Excel 2007进行统计分析。计量资料采用x ± s表示; 组间血压、心率、插管时间比较采用两独立样本t检验，组内血压、心率比较采用配对样本t检验，咽痛、声嘶比较采用χ2检验。P＜0. 05表示差异有统计学意义。
结 果
患者一般情况
40例患者全部完成试验。D组及L组患者平均年龄分别为(35. 5 ± 7. 6)和(36. 6 ± 8. 1)岁(P = 0. 662)，平均身高分别为(162. 1 ± 3. 4)和(160. 3 ± 3. 7) cm (P = 0. 114)，平均体重分别为(57. 0 ± 7. 6)和(60. 3 ± 8. 9) kg (P = 0. 214)，平均手术时间分别为(81. 8 ± 17. 7)和(82. 3 ± 18. 7) min (P = 0. 931)，两组比较差异均无统计学意义。
插管成功率和效率
40例患者均未发生气管导管误入食道。插管时间D组为(21. 6 ± 13. 4) s，L组为(27. 5 ± 19. 6) s (P = 0. 273)。
气管插管期血流动力学变化
两组患者喉镜入镜时的平均动脉压和心率比较差异均无统计学意义(P＞0. 05);两组患者出镜时的平均动脉压及心率均高于入镜时(P＜0. 05)，D组出镜时平均动脉压及心率与L组比较差异有统计学意义(P＜0. 05) (表 1)。
表 1 气管插管期两组患者血流动力学变化(x ± s)气管插管期 平均动脉压(mm Hg) 心率(次/min) D组 L组 D组 L组 入镜时 69. 3 ± 9. 0 69. 0 ± 6. 7 71. 2 ± 12. 5 70. 8 ± 8. 8 出镜时 93. 6 ± 8. 9* 86. 0 ± 11. 6* ‡ 87. 6 ± 13. 5* 78. 3 ± 9. 9* ‡ D组使用Macintosh喉镜，L组使用Shikani可视插管镜; 1 mm Hg = 0. 133 kPa; 与入镜时比较，* P＜0. 05;与D组比较，‡P＜0. 05 气管插管并发症
D组咽痛和声嘶发生率分别为5例(25%)和2例(10%)，高于L组的3例(15%)和0例，但两组比较差异无统计学意义(P＞0. 05)。
讨 论
气管插管会引起心血管系统交感反应，也称气管插管应激反应，其表现为喉镜和插管操作期间发生血压升高和心率加快，并可能诱发心律失常。目前认为三个因素与插管应激反应有关:插管工具对组织的作用力[2]，操作持续时间[2]及气管插管的次数[3]。本研究结果提示，在非困难气道女性患者中，应用Shikani可视插管镜行气管插管仍然会引起明显的心血管反应，表现为平均动脉压升高和心率增快，但Macintosh喉镜引起的心血管反应更明显。Shikani可视插管镜和Macintosh喉镜具有相似的插管成功率和插管速度。
通常麻醉医师会采取加深麻醉深度、缩短喉镜操作时间、表面麻醉等方法以减轻插管反应的强度与持续时间。不同的气道工具引起的气管插管反应也可能不同。Macintosh喉镜是经典的气管插管工具，也是多数麻醉医师最熟悉且应用最为熟练的气道工具之一。在使用Macintosh喉镜插管时需要将其镜片置于会厌上方并用力上提，此时作用在局部组织的力量会达到约5. 4 kg[4]。喉镜对牙齿的作用力也会很大，Fukuda等[5]记录下喉镜对上颌切牙的作用力最大可达到40. 2 N。视频喉镜可以显著降低这种作用力。根据Lee等[6]报道，Macintosh喉镜对上颌切牙的作用力范围是0 ~ 87. 4 N，而视频喉镜(Karl Storz，Tuttlingen)的范围是0 ~ 45. 2 N。Shikani可视插管镜是可视硬质管芯类气道工具之一，操作时不需要上提动作，从而减少了对会厌、舌根及咽部组织的机械刺激，也就减轻了患者的心血管反应，本研究得到的结果与之前的研究一致。赵诗斌等[7]发现Shikani可视插管镜正中入路经口气管插管的血流动力学反应轻于Macintosh直接喉镜气管插管。Yao等[8]发现Shikani可视插管镜的插管速度更快，并可以减轻插管时的心血管反应，减轻口咽和牙齿损伤。
Takahashi等[9]比较Macintosh喉镜对咽部刺激和气管插管通过气道时对气管的刺激，发现用直接喉镜显露声门但不插管引起的血压波动明显小于用直接喉镜显露声门并进行气管插管，因此认为血流动力学变化主要来自插管对气道的直接刺激而不是喉镜对咽部的刺激。笔者认为，Shikani可视插管镜引起的血流动力学波动是插管对气管刺激引起的，而Macintosh喉镜引起的血流动力学波动是插管对气管刺激和喉镜对咽部刺激两者之和。所以，Macintosh喉镜引起的血流动力学波动大于Shikani可视插管镜。
Yao等[8]比较Shikani可视插管镜和Macintosh喉镜后发现，Shikani可视插管镜可减轻对口咽和牙齿的损伤; 而本研究结果却显示两种方法引起的咽痛和声嘶发生率差异无显著统计学意义。造成结果不一致的原因可能是试验设计的不同:虽然本研究评估咽痛和声嘶的时间点均选在患者离开恢复室时，但Yao等术中使用瑞芬太尼，本研究使用镇痛作用更长的芬太尼，从而降低了咽痛的发生率。
气道工具操作具有主观性，操作者熟练程度对试验结果会有影响，不同的操作者可能获得不同的数据，这可能是本研究与其他研究结果有区别的原因。评估插管前后血压变化的理想方法是有创血压监测，但由于临床实际工作的限制，本研究使用的是无创血压监测，这可能导致数据的误差和延迟。本研究是在非困难气道患者得出的结果，困难气道人群的操作时间可能会增加。本研究样本量可能尚不足以体现气道并发症的统计学差异。
综上，在非困难气道女性患者中，应用Shikani可视插管镜行气管插管仍然会引起明显的心血管反应，表现为平均动脉压升高和心率增快，但不如Macintosh喉镜的波动明显。
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表 1 β干扰素-1b对患者EDSS、年复发次数、颅内增强病灶数目及血清尿酸水平的影响
时间 EDSS (中位数) 年复发次数(中位数) 颅内增强病灶数目(中位数) 尿酸(μmol/L，x ± s) 治疗前(缓解期) 2.8 0.9 1.5 222. 2 ± 28. 9 治疗后6个月 2.0 0.0 0.0 239. 4 ± 48. 7 P值 0.064 0.011 0.007 0.213 EDSS:扩展残疾状态评分 
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