骶管注射疗法中激素种类、浓度及碱化溶液选择的安全性研究
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摘要
目的：
一、糖皮质激素是骶管注射疗法中最常用的药物之一,也是最易滥用导致诸多临床意外发生的药物。糖皮质激素具有保钠排钾的作用,易导致钠水潴留,以及引起肝脏肿大和哮喘等不良反应,不同的激素引起以上不良反应的程度不同。为此,考察不同的糖皮质激素在骶管注射疗法中的安全性十分必要。但既往文献多为临床病例的报道或不同激素临床疗效的对比研究,基础研究匮乏。故本课题组设计实验一主要研究临床常用激素泼尼松、地塞米松、及曲安奈得硬膜外腔注射对SD大鼠肾上腺皮质功能及形态学的影响,为规范化的激素安全选择与药物配伍提供实验依据。
二、骶管注射疗法是从麻醉学基础上发展起来的,普遍认为骶管注射治疗腰椎间盘突出症的作用机理是通过糖皮质激素注入硬膜外腔直接阻断疼痛的传导通路,阻断化学刺激因了对神经根的刺激,并抑制无菌性炎症,消除水肿及抑制粘连而达到治疗目的,以致临床上有人随意加大局麻药或糖皮质激素的用量,以期增加临床疗效。关于麻药用量的安全性已有相关的深入研究,且已得到临床医师的重视,但关于激素的用量,由于其部分不良反应并非立即出现,比如对血糖、血脂及电解质的影响等,需要经过数天甚至数周才有一定变化,故有许多医师盲目加大激素的用量,甚至将两种激素一起使用,对于激素的用量没有严格的控制。针对以上情况设计实验二主要研究硬膜外腔注射不同浓度泼尼松对SD大鼠血糖、血脂及股骨头形态学的影响,为硬膜外注射激素的浓度选择提供实验依据。
三、目前,注射不同的复合药物用于临床治疗各种顽固性疼痛已成为疼痛治疗的常用方法之一。且运用肌电图等检查手段对骶管注射前后患者神经、肌肉功能进行的研究,已进一步证实了骶管内药物注射疗法是肯定的。常用的复合药液一般多从神经根阻滞、炎症消除、血管扩张、粘连剥离及神经营养等角度考虑,但也有学者从改变骶管内环境的pH值角度着手,在治疗药液中加入适量的碳酸氢钠直接提高pH值,通过减轻局部组织酸中毒,降低H+和局部致痛物质的生成,以增强治疗效果。根据pH值的分配学说,如果pH值越大,则离解度越小,非离子状态的局麻药物浓度就会愈高,继而抵达神经细胞发挥作用的非离子局麻药物明显增多,最终使局麻药物的起效时间和阻滞完全时间均明显缩短。这种碱化溶液疗法从临床报道看来也的确取得了不错的效果。但是此碱性液体是否会对硬膜外腔内的组织结构产生不利影响,尚缺乏基础实验的支持,故本课题组设计实验三初步地探索硬膜外腔注射碱化溶液对SD大鼠神经根功能及组织学的影响,为硬膜外注射碱化溶液提供依据。
方法：
一、将健康雄性SD大鼠60只,随机分为5组,每组12只。前3组为实验组,其中第1组为泼尼松组,硬膜外腔注射醋酸泼尼松+利多卡因+生理盐水,比例为1ml:2ml:17m1;第2组为地塞米松组,硬膜外腔注射地塞米松+利多卡因+生理盐水,比例为lml:2m1:17ml;第3组为曲安奈得组,硬膜外腔注射醋酸曲安奈得+利多卡因+生理盐水,比例为lml:2m1:17m1.第4组为对照组,硬膜外腔注射利多卡因+生理盐水,比例为2m1：18ml,各组药液用量均为1ml/kg/次。第5组为正常组,仅参与麻醉,不做其他任何处理。实验组与对照组硬膜外腔给药每周1次,连续注射3周,注射及评估方法参照文献介绍的硬膜外穿刺造模及评估方式,将药液由腰椎5、6间隙注入到大鼠硬膜外腔。第4周统时间段采取大鼠血液,离心后仔细收集上清,用大鼠皮质醇(Cortisol)ELISA试剂盒检测各组血清中皮质醇含量。并取各组大鼠双侧肾上腺固定于10%中性福尔马林溶液,常规方法脱水,石蜡包埋切片,HE染色,光学显微镜观察并测量肾上腺皮质厚度及束状带所占的比例。所有数据均用均数±标准差(x±s)表示,采用SPSS13.0统计软件进行方差分析(One-way ANOVA LSD法)进行统计处理,比较各组大鼠血清皮质醇含量均数,肾上腺皮质厚度及束状带所占比例。
二、将健康雄性SD大鼠60只,随机分为5组,每组12只。前3组为实验组,分别为泼尼松低、中、高浓度组,其中泼尼松低浓度组的药物配伍为醋酸泼尼松+利多卡因+生理盐水,用药比例为lml:2ml:17ml,泼尼松中浓度组的药物配伍为醋酸泼尼松+利多卡因+生理盐水,用药比例为2ml:2ml:16ml,泼尼松高浓度组用药配伍为醋酸泼尼松+利多卡因+生理盐水,比例为4ml:2ml:14ml。第4、5组分别为对照组和正常组。对照组硬膜外腔注射利多卡因+生理盐水,比例为2ml:18ml,各组药液用量均为lml/kg/次。第5组为正常组,仅参与麻醉,不做其他任何处理。实验组与对照组硬膜外腔给药每周1次,连续注射3周,第1次治疗前及每次治疗后1周均取血1次,连续对比观察各组的血糖(GLU)、总胆固醇(CHO)、甘油三酯(TG)的变化,于第4周用过量的10%水合氯醛麻醉处死所有实验大鼠,取双侧股骨头,福尔马林溶液固定,脱钙,清水浸泡过夜,梯度脱水,透明,浸蜡,包埋,切片,HE染色,光学显微镜下观察。所有数据均用均数±标准差(x±s)表示,采用SPSS13.0软件数据的方差分析进行分析。组内不同时间点之间采用多重比较方法(LSD方法)。用药前的组间比较采用One-Way ANOVA方差比较；用药后同一时间点的组间比较由于需要考虑用药前的因素,故采用协方差分析进行统计比较。P<0.05表示差异有统计学意义。
三、雄性SD大鼠36只,随机分为3组,每组12只。分别为实验组,即碱化溶液组,不加碱化溶液的对照组,以及正常组。碱化溶液组的药物配伍为地塞米松+利多卡因+生理盐水+碳酸氢钠,用药比例为lml:2ml:12ml:5ml,对照组的药物配伍为地塞米松+利多卡因+生理盐水,用药比例为lml:2ml:17ml,各组药液用量均为lml/kg/次。正常组仅参与麻醉,不做其他任何处理。实验组与对照组硬膜外腔给药每周1次,连续注射3周。测量实验前及第4周大鼠对机械刺激缩爪阈值,与马尾神经传导速度,并于第4周将经电生理检测完毕的大鼠取各组大鼠脊膜脊髓及神经根固定于10%中性福尔马林溶液,常规方法脱水,石蜡包埋切片,HE染色,光学显微镜观察。采用SPSS13.0统计软件进行统计分析,计量结果用均数±标准差(x±s)表示。组内治疗前后比较采用配对t检验。用药前的组间比较采用One-Way ANOVA方差比较。用药后的组间比较由于需要考虑用药前的因素,故采用协方差分析进行检验。P<0.05表示差异有统计学意义。
结果：
一、第1、4、5组均分别与第2组、3组比较,血清皮质醇差异有统计学意义(P<0.05)。各组的肾上腺组织HE染色观察测量显示,2组和3组的束状带所占皮质的比例与1、4、5组相比下降明显(P<0.01)。实验过程中动物死亡数：第3周(即第2次注射后)泼尼松组死亡大鼠1只,地塞米松组和曲安奈得组均先后死亡2只,均表现为腹部膨隆,尸检发现腹部大量腹水,肠管胀气,推测应是钠水潴留引起的心衰致死。对照组与正常组各有1只大鼠死于实验过程中麻醉药物过量。
二、(1)泼尼松高浓度组和中浓度组用药后1周GLU即明显高于其他各组；(2)高浓度组的血清CHO, TG均在用药后1周其升高趋势就开始明显高于其他各组,用药后2周达到峰值,中浓度组CHO, TG用药后2周其升高变化趋势高于低浓度组、对照组和正常组,而低浓度组相对于对照组和正常组也有轻微升高血清TG的作用；(3)高浓度组股骨头出现空骨陷窝,骨小梁排列紊乱,变短变细的情况比中、低浓度组更多见、更严重。实验过程泼尼松低浓度组和高浓度组各有1只大鼠出现钠水潴留且均死亡,对照组和正常组各有1只大鼠由于麻醉药物过量致死。钠水潴留的大鼠均表现为腹部膨隆,尸检发现腹部大量腹水,肠管胀气。
三、实验前后各组大鼠机械刺激后肢缩爪阈值及马尾神经传导速度比较差异均无统计学意义,各组神经根病理切片也未见明显损害改变。在实验过程中碱化溶液组中的钠水潴留发生率较其他组别高,有4只大鼠出现钠水潴留,其中3只死亡,而对照组中有2只出现钠水潴留且均死亡,正常组有1只大鼠由于麻醉药物过量致死。钠水潴留的大鼠均表现为腹部膨隆,尸检发现腹部大量腹水,肠管胀气,推测应均为钠水潴留引起的心衰致死。
结论：
一、硬膜外腔注射对全身影响大的长效激素,如地塞米松和醋酸曲安奈得会引起雄性SD大鼠肾上腺皮质功能减退,并导致肾上腺组织学上的萎缩改变,而使用对全身影响较小的中效激素醋酸泼尼松不会引起此类变化,可能是由于长效激素的半衰期时间较长,连续给药导致药物浓度蓄积过高,长期抑制肾上腺的正常功能所致,也可能是由于不同的激素其效价不同引起。而且醋酸泼尼松引起钠水潴留风险较低,故进行硬膜外腔激素注射治疗时,选用以局部效应为主的中效制剂醋酸泼尼松,相对于对全身影响较大的长效制剂地塞米松和醋酸曲安奈得而言更为安全。
硬膜外激素注射还存在一些少见的、潜在的、甚至严重的神经系统、周围组织器官及其他系统等并发症,如脑和脊髓梗塞、硬膜外血肿、椎间隙感染、月经紊乱、过敏等。部分并发症机制仍不清楚,有待进一步探讨。面对以上的不安全因素,应该尽快制定一套标准的规范化操作程序来指导临床应用。在以后的科研实践中关注硬膜外注射的基础研究,并在将来的临床试验中运用标准统一的疗效监测指标与时间评估终点,且长期观察临床反应的相关因素,并比较不同组别之间的效果差异,建议多个临床中心联合研究,集合有效的资料进行循征医学分析,用科学的结论指导临床应用。
二、高浓度泼尼松硬膜外腔注射对血糖、血脂产生不良影响,并使股骨头产生类似坏死的病理学变化,故行硬膜外腔类固醇激素注射治疗疼痛相关疾病时,应注意严格把握适应症,对于糖尿病患者,肥胖或血脂较高的患者,以及严重的骨质疏松,主要靠单侧股骨头负重,应力较为集中的患者应慎用硬膜外类固醇激素治疗,并注意不可多次注射。在多次硬膜外腔注射的其他患者中,应注意常规监测血糖、血脂、血小板及血浆黏度等这些对于激素性股骨头坏死防治有重要参考价值的便捷指标。就目前的研究结果,硬膜外腔少次低浓度的激素使用是更为安全的选择。
三、碱化药液组、常规硬膜外注射药液的普通对照组在实验前后神经根功能未发生明显敏感或迟钝的改变,也未见到明显的神经根组织学损害。表明本实验组及对照组的药物组成并不会造成明显的神经根功能及组织学影响,是相对安全的药物选择,即碱化溶液骶管注射不会造成神经根功能及组织学的有害影响,可作为安全的配方选择。但由于长效激素有易导致钠水潴留的可能,若再加入碱化溶液更容易导致体内电解质及酸碱平衡的紊乱,从而引发钠水潴留或使钠水潴留的情况加重。考虑到钠水潴留风险的存在,相信通过减少目前临床常规的5%碳酸氢钠5ml的用量能降低此类风险的发生,至于具体的理想用量需进一步的基础实验及临床研究指导,从而更好地在安全的前提下发挥其临床价值。
1. Objective:
1.1Glucocorticoids are a class of the most commonly used drugs in the caudal injection therapy, but also most vulnerable to be abused leading to many clinical accidents. Glucocorticoids have a role to save the sodium and excrete potassium, easily lead to sodium retention, as well as the adverse reactions such as liver swelling and asthma. And different hormones cause adverse reactions in varying degrees. With regards to this, investigating the safety of different glucocorticoids in caudal injection therapy is necessary. However, previous literatures were just reports of clinical cases or comparative study of the clinical efficacy in different hormones, lack of basic research. So our group designed experiment1in major to study the effects on adrenocortical function and morphology of Sprague-Dawley(SD) rats treating with epidural steroid injection by prednisone, dexamethasone(DXM), triamcinolone acetonide, commonly used in clinical, providing the experimental basis for normalization of hormone security selection and drug compatibility.
1.2Caudal injection therapy developed from the basis of anesthesiology. And we generally considered that the mechanism of caudal injection in the treatment of lumbar disc herniation was due to glucocorticoids into the epidural space directly blocking the pain pathway,blocking stimulation of the nerve root by chemical-stimulating factor and inhibition of inflammation, elimination of edema as well as inhibition of adhesion. So that in clinical some people arbitrarily increased the amount of local anesthetic or glucocorticoid, in order to improve clinical efficacy. Security on the amount of local anesthetic has been related to in-depth study, and the attention of clinicians. But on the amount of hormones, because of some of its adverse effects not appearing immediately, such as glucose, lipids and electrolytes, usually a few days or even weeks before a certain change need to go through a few days or even weeks before a certain change, many physicians blindly increase the amount of hormones, even with two hormones used together. For the amount of hormone had not been strictly controlled. So our group designed experiment2in major to study the effects on glucose, lipids and morphology of the femoral head of Sprague-Dawley(SD) rats with epidural injection by different concentrations of prednisone, providing experimental evidence for the selection of concentration in epidural steroid injections.
1.3At present, injection of compound drugs for the clinical treatment of various intractable pain has become a common method of pain treatment. And through testing and studying the patients'nerve, muscle function before and after caudal injection with EMG and other inspection methods, the caudal drug injection therapy has been further confirmed in the affirmative. And more generally from the view of blocking nerve root, eliminating inflammation, dilate blood vessels, peel adhesion and neurotrophic to consider the composition of the commonly used composite liquid, but there were also scholars from the point of changing the pH value of the sacral canal environment, by adding an appropriate amount of sodium bicarbonate in the treatment of liquid to raise the pH directly, by reducing local tissue acidosis, to reduce the generation of H+and substances that causing local pain, in order to enhance the therapeutic effect. According to the doctrine of the distribution of pH, if the pH value is the greater, the degree of dissociation will be smaller, the higher of the local anesthetic concentration of non-ionic state, and the local anesthetic of non-ionic playing a role in nerve cells increased significantly, and finally the onset time and completely block time of local anesthesia drug were much shorter. This alkalization solution therapy obtained good results from the clinical reports. But whether this alkaline liquid will be adverse to the tissue of epidural space or not, still lack the support from the basic experiments. So our group designed experiment3preliminary to study the effects on function and histology of nerve root in SD rats with epidural injection by alkaline solution, providing experimental evidence for epidural injection by alkaline solution.
2. Methods:
2.1A total of70male SD rats were randomly devided into6groups, and every group has12rats. First3groups are experimental groups, including group1, just prednisone group, epidural injection of prednisone acetate+lidocaine+saline, the ratio of1ml:2ml:17ml; group2, just dexamethasone group, epidural injection of dexamethasone+lidocaine+saline, the ratio of1ml:2ml:17ml; group3, just triamcinolone acetonide group, epidural injection of triamcinolone acetonide+lidocaine+saline, the ratio of1ml:2ml:17ml. Group4, just the control group, epidural injection of lidocaine+saline, the ratio of2ml:18ml, each liquid dosage is1ml/kg/time. Group5, just the normal group, only involved in anesthesia, without any other processing. Experimental group and control group were weekly treated with epidural injection, for three consecutive weeks. Injection and assessment methods referred to the epidural modeling and assessment methods described in literature, and liquid injected into the epidural space in rats by the5,6lumbar intervertebral space. The fourth week of a unified time to take the blood of rats, carefully collect the supernatant after centrifugation, and detect the serum cortisol levels by the rats cortisol (Cortisol) ELISA kit. And take the rats of bilateral adrenal glands fixed in10%neutral buffered formalin, conventional methods of dehydration, paraffin-embedded sections, HE staining and measure adrenal cortex thickness and the proportion of fascicular zone. All data were used to mean±standard deviation (x±s), using SPSS13.0statistical software for analysis of variance (One-way ANOVA of LSD method) for statistical processing, comparing each group of rats' serum cortisol levels, adrenal cortex thickness and the proportion of the fascicular zone.
2.2A total of60male SD rats were randomly devided into5groups, and every group has12rats. First3groups were experimental groups, including groups with low, medium and high concentrations of prednisone, and the drugs of low concentration group of prednisone combined as prednisone acetate+lidocaine+saline, medication ratio of1ml:2ml:17ml; the drugs of medium concentration group of prednisone combined as prednisone acetate+lidocaine+saline, medication ratio of2ml:2ml:16ml; the drugs of high concentration group of prednisone combined as prednisone acetate+lidocaine+saline, the ratio4ml:2ml:14ml. group4and group5were the control group and the normal group. The control group, epidural injection of lidocaine+saline, the ratio of2ml:18ml, each liquid dosage is1ml/kg/time. Group5, just the normal group, only involved in anesthesia, without any other processing. Experimental group and control group were weekly treated with epidural injection, for three consecutive weeks, and were bleeded before the first treatment and one week after each treatment. Compare the continuous changes of glucose(GLU), total cholesterol(CHO), triglyceride (TG) in each group. All experimental rats were sacrificed with10%excess chloral hydrate anesthesia at the4th week, the femoral head were fixed in formalin, decalcified, soaked in water overnight, dehydrated, transparent, dip wax embedded, sectioned, HE staining and observed under the microscope. All data were used to mean±standard deviation (x±s), using Analysis of variance of the data for analyzing with SPSS13.0software. Within group at different time points were compared using Post Hoc Multiple comparisons (LSD method). Between the different groups before treatment were compared using One-Way ANOVA variance; the same point in time between the different groups after treatment, because of the need to consider the factors before treatment, the use of Analysis of Covariance was necessary. P<0.05indicated that the difference was statistically significance.
2.3A total of36male SD rats were randomly devided into3groups, and every group has12rats. There were experimental group-just alkaline solution group, control group-just without alkaline solution, and the normal group. Alkalization solution group of drugs combined as dexamethasone+lidocaine+saline+sodium bicarbonate, medication ratio of1ml:2ml:12ml:5ml, the control group drugs combined dexamethasone+lidocaine+saline, medication ratio of1ml:2ml:17ml, the liquid dosage are1ml/kg/time. Normal group involved in anesthesia, without any other processing. Experimental group and control group were weekly treated with epidural injection, for three consecutive weeks. Measure paw withdrawal threshold to mechanical stimulation and cauda equina nerve conduction velocity of the rats before experiment and the forth week. By electrophysiological testing was completed in the forth week, take the rats spina cord and nerve roots fixed in10%neutral buffered formalin, conventional methods of dehydration, paraffin-embedded sections, HE staining, observed by optical microscope. Using SPSS13.0statistical software for statistical analysis, and measurement results were used to mean±standard deviation (x±s). Whingroup before and after treatment were compared using Paired-Samples T Test. Between the different groups before treatment were compared using One-Way ANOVA variance; comparison between the different groups after treatment, because of the need to consider the factors before treatment, the use of Analysis of Covariance was necessary. P<0.05indicated that the difference was statistically significance.
3. Results:
3.1There is statistical significance difference in serum cortisol between group1,4,5and group2,3(P<0.05). Adrenal gland in each group of HE staining showed that group2and group3the proportion of fascicular zone in cortex comparing with1,4,5decreased significantly (P<0.01). Animals died during the experiment:the third week(just after the second treatment), prednisone group had died1rat, dexamethasone group and triamcinolone acetonide group had died2rats, all with distended abdomen. Autopsy revealed massive abdominal ascites, intestinal flatulence, with speculating for heart failure death be caused by sodium and water retention. The control group and normal group both also had died1rat due to narcotic drugs overdose during experiment.
3.2Just one week after treatment, GLU in the high concentration and the medium concentration group of prednisone was significantly higher than other groups;(2) Just one week after treatment, the increasing trend of serum CHO, TG in the high concentration group was significantly higher than other groups, peaked in2weeks after treatment, the increasing trend of serum CHO, TG in the medium concentration group, after2weeks of treatment, was higher than low concentration group, control group and normal group. While serum TG was also slightly elevated in the low concentration group compare to the control group and normal group;(3) the situation of empty lacunae in femoral head, and disorder, Shorter, thinner of bone trabecula in the high concentration group was more common and more serious than other groups. During the experiment, the low concentration group and high concentration group of prednisone both had died1rats caused by sodium and water retention. The control group and normal group both also had died1rat due to narcotic drugs overdose. Rats with Sodium and water retention all showed distended abdomen, the autopsy found that the abdomen with massive ascites, intestinal flatulence.
3.3Before and after the experiment, there was no statistically significant differences in the posterior limb's retracting threshold for mechanical stimulation of rats among each group, also was the cauda equina'conduction velocity in each group. There was no obvious damage change in pathological section of each group'nerve root. During the experiment, the rate of sodium and water retention in alkaline solution group was higher than other groups, and4rats appeared to sodium and water retention, of which3died, while the control group2rats appeared to sodium and water retention and all died. The normal group had died1rat due to narcotic drugs overdose. Rats with Sodium and water retention all showed distended abdomen, the autopsy found that the abdomen with massive ascites, intestinal flatulence, with speculating for heart failure death be caused by sodium and water retention.
4. Conclusions:
4.1Epidural injection of long-term hormone with systemic impact, such as dexamethasone and triamcinolone acetonide, might cause adrenal insufficiency and adrenal atrophy morphological changes in male SD rats, but middle-term hormones with less systemic impact as prednisone did not cause such similar changes. May be due to the longer half-life time of the long-term hormone, high accumulation of the drug concentration caused by continuous administration, and long-term inhibition of the normal function of the adrenal gland, may also be caused by different potency due to different hormone kinds. And prednisone acetate caused the lower risk of sodium and water retention. Therefore, in epidural steroid injection therapy, selection of middle-term hormones with mainly local effects as prednisone acetate was safer than long-term hormone with more systemic impact, such as dexamethasone and triamcinolone acetonide.
In epidural steroid injection, there is a rare, potentially, even serious complications of the nervous system, the surrounding tissue, organs and other systems, etc., such as brain and spinal cord infarct, epidural hematoma, disc space infection, menstrual disorders, allergies and so on. The mechanism of some complications remains unclear and needs further study. Faced with the above factors of insecurity, we should develop a standard and reasonable operating procedures to guide the clinical application as soon as possible. Concerned about basic research of the epidural injection in the later practice of scientific research. And use of a unified, standard treatment monitoring indicators and time of assessment endpoints in future clinical trials, with long-term observation of the clinical response to the relevant factors, and comparing the effect of the difference between the different groups. It is recommended that multiple clinical centers together to study, collection of valid data to evidence-medical analysis, using the scientific conclusions to guide the clinical application.
4.2Epidural injection of high concentrations of prednisone has a negative impact on glucose, lipids, and made the pathological changes of similar necrosis on the femoral head. Therefore, we should strictly control indications of epidural steroid injection in treatment of pain-related diseases. For patients with diabetes, obesity or hyperlipemia, as well as severe osteoporosis, mainly relying on the unilateral femoral head to load, with more concentrated stress should be used with caution in epidural steroid therapy, and prohibited to multiple injections. In other patients with repeated epidural injection, should pay attention to the routine monitoring of blood glucose, blood lipids, platelets and plasma viscosity, as convenient indicators of important reference value for the prevention and treatment of femoral head necrosis. Concerned about the results of the present study, the less low concentrations of steroid using in the epidural space is a much safer choice.
4.3In alkaline solution group, and the routine epidural injection liquid of normal control group, the nerve root function did not occur significantly sensitive or slow changes, and there was not obvious histological damage of nerve root before and after experiment. Showed that drug composition of the experimental group and control group did not cause significant damage to nerve root function and histology, which was a relatively safe drug of choice. Namely the alkaline solution of caudal injection will not cause the harmful effects of nerve root function and histology, this formula can be used as a safe choice. However, due to long-term hormone maybe easily leading to sodium and water retention, if we join the alkalization of the solution will more easily lead to balance disorders in electrolyte and acid-base of the body, causing sodium and water retention or aggravating circumstances. Taking into account the existence of the risk of sodium and water retention, I believe that by reducing the current clinical practical dosage of5%bicarbonate5ml can reduce the occurrence of such risks. As for the ideal amount, we need further basic experimental and clinical research as guidance, in order to better play its clinical value under the premise of safety.
一、糖皮质激素是骶管注射疗法中最常用的药物之一,也是最易滥用导致诸多临床意外发生的药物。糖皮质激素具有保钠排钾的作用,易导致钠水潴留,以及引起肝脏肿大和哮喘等不良反应,不同的激素引起以上不良反应的程度不同。为此,考察不同的糖皮质激素在骶管注射疗法中的安全性十分必要。但既往文献多为临床病例的报道或不同激素临床疗效的对比研究,基础研究匮乏。故本课题组设计实验一主要研究临床常用激素泼尼松、地塞米松、及曲安奈得硬膜外腔注射对SD大鼠肾上腺皮质功能及形态学的影响,为规范化的激素安全选择与药物配伍提供实验依据。
二、骶管注射疗法是从麻醉学基础上发展起来的,普遍认为骶管注射治疗腰椎间盘突出症的作用机理是通过糖皮质激素注入硬膜外腔直接阻断疼痛的传导通路,阻断化学刺激因了对神经根的刺激,并抑制无菌性炎症,消除水肿及抑制粘连而达到治疗目的,以致临床上有人随意加大局麻药或糖皮质激素的用量,以期增加临床疗效。关于麻药用量的安全性已有相关的深入研究,且已得到临床医师的重视,但关于激素的用量,由于其部分不良反应并非立即出现,比如对血糖、血脂及电解质的影响等,需要经过数天甚至数周才有一定变化,故有许多医师盲目加大激素的用量,甚至将两种激素一起使用,对于激素的用量没有严格的控制。针对以上情况设计实验二主要研究硬膜外腔注射不同浓度泼尼松对SD大鼠血糖、血脂及股骨头形态学的影响,为硬膜外注射激素的浓度选择提供实验依据。
三、目前,注射不同的复合药物用于临床治疗各种顽固性疼痛已成为疼痛治疗的常用方法之一。且运用肌电图等检查手段对骶管注射前后患者神经、肌肉功能进行的研究,已进一步证实了骶管内药物注射疗法是肯定的。常用的复合药液一般多从神经根阻滞、炎症消除、血管扩张、粘连剥离及神经营养等角度考虑,但也有学者从改变骶管内环境的pH值角度着手,在治疗药液中加入适量的碳酸氢钠直接提高pH值,通过减轻局部组织酸中毒,降低H+和局部致痛物质的生成,以增强治疗效果。根据pH值的分配学说,如果pH值越大,则离解度越小,非离子状态的局麻药物浓度就会愈高,继而抵达神经细胞发挥作用的非离子局麻药物明显增多,最终使局麻药物的起效时间和阻滞完全时间均明显缩短。这种碱化溶液疗法从临床报道看来也的确取得了不错的效果。但是此碱性液体是否会对硬膜外腔内的组织结构产生不利影响,尚缺乏基础实验的支持,故本课题组设计实验三初步地探索硬膜外腔注射碱化溶液对SD大鼠神经根功能及组织学的影响,为硬膜外注射碱化溶液提供依据。
方法：
一、将健康雄性SD大鼠60只,随机分为5组,每组12只。前3组为实验组,其中第1组为泼尼松组,硬膜外腔注射醋酸泼尼松+利多卡因+生理盐水,比例为1ml:2ml:17m1;第2组为地塞米松组,硬膜外腔注射地塞米松+利多卡因+生理盐水,比例为lml:2m1:17ml;第3组为曲安奈得组,硬膜外腔注射醋酸曲安奈得+利多卡因+生理盐水,比例为lml:2m1:17m1.第4组为对照组,硬膜外腔注射利多卡因+生理盐水,比例为2m1：18ml,各组药液用量均为1ml/kg/次。第5组为正常组,仅参与麻醉,不做其他任何处理。实验组与对照组硬膜外腔给药每周1次,连续注射3周,注射及评估方法参照文献介绍的硬膜外穿刺造模及评估方式,将药液由腰椎5、6间隙注入到大鼠硬膜外腔。第4周统时间段采取大鼠血液,离心后仔细收集上清,用大鼠皮质醇(Cortisol)ELISA试剂盒检测各组血清中皮质醇含量。并取各组大鼠双侧肾上腺固定于10%中性福尔马林溶液,常规方法脱水,石蜡包埋切片,HE染色,光学显微镜观察并测量肾上腺皮质厚度及束状带所占的比例。所有数据均用均数±标准差(x±s)表示,采用SPSS13.0统计软件进行方差分析(One-way ANOVA LSD法)进行统计处理,比较各组大鼠血清皮质醇含量均数,肾上腺皮质厚度及束状带所占比例。
二、将健康雄性SD大鼠60只,随机分为5组,每组12只。前3组为实验组,分别为泼尼松低、中、高浓度组,其中泼尼松低浓度组的药物配伍为醋酸泼尼松+利多卡因+生理盐水,用药比例为lml:2ml:17ml,泼尼松中浓度组的药物配伍为醋酸泼尼松+利多卡因+生理盐水,用药比例为2ml:2ml:16ml,泼尼松高浓度组用药配伍为醋酸泼尼松+利多卡因+生理盐水,比例为4ml:2ml:14ml。第4、5组分别为对照组和正常组。对照组硬膜外腔注射利多卡因+生理盐水,比例为2ml:18ml,各组药液用量均为lml/kg/次。第5组为正常组,仅参与麻醉,不做其他任何处理。实验组与对照组硬膜外腔给药每周1次,连续注射3周,第1次治疗前及每次治疗后1周均取血1次,连续对比观察各组的血糖(GLU)、总胆固醇(CHO)、甘油三酯(TG)的变化,于第4周用过量的10%水合氯醛麻醉处死所有实验大鼠,取双侧股骨头,福尔马林溶液固定,脱钙,清水浸泡过夜,梯度脱水,透明,浸蜡,包埋,切片,HE染色,光学显微镜下观察。所有数据均用均数±标准差(x±s)表示,采用SPSS13.0软件数据的方差分析进行分析。组内不同时间点之间采用多重比较方法(LSD方法)。用药前的组间比较采用One-Way ANOVA方差比较；用药后同一时间点的组间比较由于需要考虑用药前的因素,故采用协方差分析进行统计比较。P<0.05表示差异有统计学意义。
三、雄性SD大鼠36只,随机分为3组,每组12只。分别为实验组,即碱化溶液组,不加碱化溶液的对照组,以及正常组。碱化溶液组的药物配伍为地塞米松+利多卡因+生理盐水+碳酸氢钠,用药比例为lml:2ml:12ml:5ml,对照组的药物配伍为地塞米松+利多卡因+生理盐水,用药比例为lml:2ml:17ml,各组药液用量均为lml/kg/次。正常组仅参与麻醉,不做其他任何处理。实验组与对照组硬膜外腔给药每周1次,连续注射3周。测量实验前及第4周大鼠对机械刺激缩爪阈值,与马尾神经传导速度,并于第4周将经电生理检测完毕的大鼠取各组大鼠脊膜脊髓及神经根固定于10%中性福尔马林溶液,常规方法脱水,石蜡包埋切片,HE染色,光学显微镜观察。采用SPSS13.0统计软件进行统计分析,计量结果用均数±标准差(x±s)表示。组内治疗前后比较采用配对t检验。用药前的组间比较采用One-Way ANOVA方差比较。用药后的组间比较由于需要考虑用药前的因素,故采用协方差分析进行检验。P<0.05表示差异有统计学意义。
结果：
一、第1、4、5组均分别与第2组、3组比较,血清皮质醇差异有统计学意义(P<0.05)。各组的肾上腺组织HE染色观察测量显示,2组和3组的束状带所占皮质的比例与1、4、5组相比下降明显(P<0.01)。实验过程中动物死亡数：第3周(即第2次注射后)泼尼松组死亡大鼠1只,地塞米松组和曲安奈得组均先后死亡2只,均表现为腹部膨隆,尸检发现腹部大量腹水,肠管胀气,推测应是钠水潴留引起的心衰致死。对照组与正常组各有1只大鼠死于实验过程中麻醉药物过量。
二、(1)泼尼松高浓度组和中浓度组用药后1周GLU即明显高于其他各组；(2)高浓度组的血清CHO, TG均在用药后1周其升高趋势就开始明显高于其他各组,用药后2周达到峰值,中浓度组CHO, TG用药后2周其升高变化趋势高于低浓度组、对照组和正常组,而低浓度组相对于对照组和正常组也有轻微升高血清TG的作用；(3)高浓度组股骨头出现空骨陷窝,骨小梁排列紊乱,变短变细的情况比中、低浓度组更多见、更严重。实验过程泼尼松低浓度组和高浓度组各有1只大鼠出现钠水潴留且均死亡,对照组和正常组各有1只大鼠由于麻醉药物过量致死。钠水潴留的大鼠均表现为腹部膨隆,尸检发现腹部大量腹水,肠管胀气。
三、实验前后各组大鼠机械刺激后肢缩爪阈值及马尾神经传导速度比较差异均无统计学意义,各组神经根病理切片也未见明显损害改变。在实验过程中碱化溶液组中的钠水潴留发生率较其他组别高,有4只大鼠出现钠水潴留,其中3只死亡,而对照组中有2只出现钠水潴留且均死亡,正常组有1只大鼠由于麻醉药物过量致死。钠水潴留的大鼠均表现为腹部膨隆,尸检发现腹部大量腹水,肠管胀气,推测应均为钠水潴留引起的心衰致死。
结论：
一、硬膜外腔注射对全身影响大的长效激素,如地塞米松和醋酸曲安奈得会引起雄性SD大鼠肾上腺皮质功能减退,并导致肾上腺组织学上的萎缩改变,而使用对全身影响较小的中效激素醋酸泼尼松不会引起此类变化,可能是由于长效激素的半衰期时间较长,连续给药导致药物浓度蓄积过高,长期抑制肾上腺的正常功能所致,也可能是由于不同的激素其效价不同引起。而且醋酸泼尼松引起钠水潴留风险较低,故进行硬膜外腔激素注射治疗时,选用以局部效应为主的中效制剂醋酸泼尼松,相对于对全身影响较大的长效制剂地塞米松和醋酸曲安奈得而言更为安全。
硬膜外激素注射还存在一些少见的、潜在的、甚至严重的神经系统、周围组织器官及其他系统等并发症,如脑和脊髓梗塞、硬膜外血肿、椎间隙感染、月经紊乱、过敏等。部分并发症机制仍不清楚,有待进一步探讨。面对以上的不安全因素,应该尽快制定一套标准的规范化操作程序来指导临床应用。在以后的科研实践中关注硬膜外注射的基础研究,并在将来的临床试验中运用标准统一的疗效监测指标与时间评估终点,且长期观察临床反应的相关因素,并比较不同组别之间的效果差异,建议多个临床中心联合研究,集合有效的资料进行循征医学分析,用科学的结论指导临床应用。
二、高浓度泼尼松硬膜外腔注射对血糖、血脂产生不良影响,并使股骨头产生类似坏死的病理学变化,故行硬膜外腔类固醇激素注射治疗疼痛相关疾病时,应注意严格把握适应症,对于糖尿病患者,肥胖或血脂较高的患者,以及严重的骨质疏松,主要靠单侧股骨头负重,应力较为集中的患者应慎用硬膜外类固醇激素治疗,并注意不可多次注射。在多次硬膜外腔注射的其他患者中,应注意常规监测血糖、血脂、血小板及血浆黏度等这些对于激素性股骨头坏死防治有重要参考价值的便捷指标。就目前的研究结果,硬膜外腔少次低浓度的激素使用是更为安全的选择。
三、碱化药液组、常规硬膜外注射药液的普通对照组在实验前后神经根功能未发生明显敏感或迟钝的改变,也未见到明显的神经根组织学损害。表明本实验组及对照组的药物组成并不会造成明显的神经根功能及组织学影响,是相对安全的药物选择,即碱化溶液骶管注射不会造成神经根功能及组织学的有害影响,可作为安全的配方选择。但由于长效激素有易导致钠水潴留的可能,若再加入碱化溶液更容易导致体内电解质及酸碱平衡的紊乱,从而引发钠水潴留或使钠水潴留的情况加重。考虑到钠水潴留风险的存在,相信通过减少目前临床常规的5%碳酸氢钠5ml的用量能降低此类风险的发生,至于具体的理想用量需进一步的基础实验及临床研究指导,从而更好地在安全的前提下发挥其临床价值。
1. Objective:
1.1Glucocorticoids are a class of the most commonly used drugs in the caudal injection therapy, but also most vulnerable to be abused leading to many clinical accidents. Glucocorticoids have a role to save the sodium and excrete potassium, easily lead to sodium retention, as well as the adverse reactions such as liver swelling and asthma. And different hormones cause adverse reactions in varying degrees. With regards to this, investigating the safety of different glucocorticoids in caudal injection therapy is necessary. However, previous literatures were just reports of clinical cases or comparative study of the clinical efficacy in different hormones, lack of basic research. So our group designed experiment1in major to study the effects on adrenocortical function and morphology of Sprague-Dawley(SD) rats treating with epidural steroid injection by prednisone, dexamethasone(DXM), triamcinolone acetonide, commonly used in clinical, providing the experimental basis for normalization of hormone security selection and drug compatibility.
1.2Caudal injection therapy developed from the basis of anesthesiology. And we generally considered that the mechanism of caudal injection in the treatment of lumbar disc herniation was due to glucocorticoids into the epidural space directly blocking the pain pathway,blocking stimulation of the nerve root by chemical-stimulating factor and inhibition of inflammation, elimination of edema as well as inhibition of adhesion. So that in clinical some people arbitrarily increased the amount of local anesthetic or glucocorticoid, in order to improve clinical efficacy. Security on the amount of local anesthetic has been related to in-depth study, and the attention of clinicians. But on the amount of hormones, because of some of its adverse effects not appearing immediately, such as glucose, lipids and electrolytes, usually a few days or even weeks before a certain change need to go through a few days or even weeks before a certain change, many physicians blindly increase the amount of hormones, even with two hormones used together. For the amount of hormone had not been strictly controlled. So our group designed experiment2in major to study the effects on glucose, lipids and morphology of the femoral head of Sprague-Dawley(SD) rats with epidural injection by different concentrations of prednisone, providing experimental evidence for the selection of concentration in epidural steroid injections.
1.3At present, injection of compound drugs for the clinical treatment of various intractable pain has become a common method of pain treatment. And through testing and studying the patients'nerve, muscle function before and after caudal injection with EMG and other inspection methods, the caudal drug injection therapy has been further confirmed in the affirmative. And more generally from the view of blocking nerve root, eliminating inflammation, dilate blood vessels, peel adhesion and neurotrophic to consider the composition of the commonly used composite liquid, but there were also scholars from the point of changing the pH value of the sacral canal environment, by adding an appropriate amount of sodium bicarbonate in the treatment of liquid to raise the pH directly, by reducing local tissue acidosis, to reduce the generation of H+and substances that causing local pain, in order to enhance the therapeutic effect. According to the doctrine of the distribution of pH, if the pH value is the greater, the degree of dissociation will be smaller, the higher of the local anesthetic concentration of non-ionic state, and the local anesthetic of non-ionic playing a role in nerve cells increased significantly, and finally the onset time and completely block time of local anesthesia drug were much shorter. This alkalization solution therapy obtained good results from the clinical reports. But whether this alkaline liquid will be adverse to the tissue of epidural space or not, still lack the support from the basic experiments. So our group designed experiment3preliminary to study the effects on function and histology of nerve root in SD rats with epidural injection by alkaline solution, providing experimental evidence for epidural injection by alkaline solution.
2. Methods:
2.1A total of70male SD rats were randomly devided into6groups, and every group has12rats. First3groups are experimental groups, including group1, just prednisone group, epidural injection of prednisone acetate+lidocaine+saline, the ratio of1ml:2ml:17ml; group2, just dexamethasone group, epidural injection of dexamethasone+lidocaine+saline, the ratio of1ml:2ml:17ml; group3, just triamcinolone acetonide group, epidural injection of triamcinolone acetonide+lidocaine+saline, the ratio of1ml:2ml:17ml. Group4, just the control group, epidural injection of lidocaine+saline, the ratio of2ml:18ml, each liquid dosage is1ml/kg/time. Group5, just the normal group, only involved in anesthesia, without any other processing. Experimental group and control group were weekly treated with epidural injection, for three consecutive weeks. Injection and assessment methods referred to the epidural modeling and assessment methods described in literature, and liquid injected into the epidural space in rats by the5,6lumbar intervertebral space. The fourth week of a unified time to take the blood of rats, carefully collect the supernatant after centrifugation, and detect the serum cortisol levels by the rats cortisol (Cortisol) ELISA kit. And take the rats of bilateral adrenal glands fixed in10%neutral buffered formalin, conventional methods of dehydration, paraffin-embedded sections, HE staining and measure adrenal cortex thickness and the proportion of fascicular zone. All data were used to mean±standard deviation (x±s), using SPSS13.0statistical software for analysis of variance (One-way ANOVA of LSD method) for statistical processing, comparing each group of rats' serum cortisol levels, adrenal cortex thickness and the proportion of the fascicular zone.
2.2A total of60male SD rats were randomly devided into5groups, and every group has12rats. First3groups were experimental groups, including groups with low, medium and high concentrations of prednisone, and the drugs of low concentration group of prednisone combined as prednisone acetate+lidocaine+saline, medication ratio of1ml:2ml:17ml; the drugs of medium concentration group of prednisone combined as prednisone acetate+lidocaine+saline, medication ratio of2ml:2ml:16ml; the drugs of high concentration group of prednisone combined as prednisone acetate+lidocaine+saline, the ratio4ml:2ml:14ml. group4and group5were the control group and the normal group. The control group, epidural injection of lidocaine+saline, the ratio of2ml:18ml, each liquid dosage is1ml/kg/time. Group5, just the normal group, only involved in anesthesia, without any other processing. Experimental group and control group were weekly treated with epidural injection, for three consecutive weeks, and were bleeded before the first treatment and one week after each treatment. Compare the continuous changes of glucose(GLU), total cholesterol(CHO), triglyceride (TG) in each group. All experimental rats were sacrificed with10%excess chloral hydrate anesthesia at the4th week, the femoral head were fixed in formalin, decalcified, soaked in water overnight, dehydrated, transparent, dip wax embedded, sectioned, HE staining and observed under the microscope. All data were used to mean±standard deviation (x±s), using Analysis of variance of the data for analyzing with SPSS13.0software. Within group at different time points were compared using Post Hoc Multiple comparisons (LSD method). Between the different groups before treatment were compared using One-Way ANOVA variance; the same point in time between the different groups after treatment, because of the need to consider the factors before treatment, the use of Analysis of Covariance was necessary. P<0.05indicated that the difference was statistically significance.
2.3A total of36male SD rats were randomly devided into3groups, and every group has12rats. There were experimental group-just alkaline solution group, control group-just without alkaline solution, and the normal group. Alkalization solution group of drugs combined as dexamethasone+lidocaine+saline+sodium bicarbonate, medication ratio of1ml:2ml:12ml:5ml, the control group drugs combined dexamethasone+lidocaine+saline, medication ratio of1ml:2ml:17ml, the liquid dosage are1ml/kg/time. Normal group involved in anesthesia, without any other processing. Experimental group and control group were weekly treated with epidural injection, for three consecutive weeks. Measure paw withdrawal threshold to mechanical stimulation and cauda equina nerve conduction velocity of the rats before experiment and the forth week. By electrophysiological testing was completed in the forth week, take the rats spina cord and nerve roots fixed in10%neutral buffered formalin, conventional methods of dehydration, paraffin-embedded sections, HE staining, observed by optical microscope. Using SPSS13.0statistical software for statistical analysis, and measurement results were used to mean±standard deviation (x±s). Whingroup before and after treatment were compared using Paired-Samples T Test. Between the different groups before treatment were compared using One-Way ANOVA variance; comparison between the different groups after treatment, because of the need to consider the factors before treatment, the use of Analysis of Covariance was necessary. P<0.05indicated that the difference was statistically significance.
3. Results:
3.1There is statistical significance difference in serum cortisol between group1,4,5and group2,3(P<0.05). Adrenal gland in each group of HE staining showed that group2and group3the proportion of fascicular zone in cortex comparing with1,4,5decreased significantly (P<0.01). Animals died during the experiment:the third week(just after the second treatment), prednisone group had died1rat, dexamethasone group and triamcinolone acetonide group had died2rats, all with distended abdomen. Autopsy revealed massive abdominal ascites, intestinal flatulence, with speculating for heart failure death be caused by sodium and water retention. The control group and normal group both also had died1rat due to narcotic drugs overdose during experiment.
3.2Just one week after treatment, GLU in the high concentration and the medium concentration group of prednisone was significantly higher than other groups;(2) Just one week after treatment, the increasing trend of serum CHO, TG in the high concentration group was significantly higher than other groups, peaked in2weeks after treatment, the increasing trend of serum CHO, TG in the medium concentration group, after2weeks of treatment, was higher than low concentration group, control group and normal group. While serum TG was also slightly elevated in the low concentration group compare to the control group and normal group;(3) the situation of empty lacunae in femoral head, and disorder, Shorter, thinner of bone trabecula in the high concentration group was more common and more serious than other groups. During the experiment, the low concentration group and high concentration group of prednisone both had died1rats caused by sodium and water retention. The control group and normal group both also had died1rat due to narcotic drugs overdose. Rats with Sodium and water retention all showed distended abdomen, the autopsy found that the abdomen with massive ascites, intestinal flatulence.
3.3Before and after the experiment, there was no statistically significant differences in the posterior limb's retracting threshold for mechanical stimulation of rats among each group, also was the cauda equina'conduction velocity in each group. There was no obvious damage change in pathological section of each group'nerve root. During the experiment, the rate of sodium and water retention in alkaline solution group was higher than other groups, and4rats appeared to sodium and water retention, of which3died, while the control group2rats appeared to sodium and water retention and all died. The normal group had died1rat due to narcotic drugs overdose. Rats with Sodium and water retention all showed distended abdomen, the autopsy found that the abdomen with massive ascites, intestinal flatulence, with speculating for heart failure death be caused by sodium and water retention.
4. Conclusions:
4.1Epidural injection of long-term hormone with systemic impact, such as dexamethasone and triamcinolone acetonide, might cause adrenal insufficiency and adrenal atrophy morphological changes in male SD rats, but middle-term hormones with less systemic impact as prednisone did not cause such similar changes. May be due to the longer half-life time of the long-term hormone, high accumulation of the drug concentration caused by continuous administration, and long-term inhibition of the normal function of the adrenal gland, may also be caused by different potency due to different hormone kinds. And prednisone acetate caused the lower risk of sodium and water retention. Therefore, in epidural steroid injection therapy, selection of middle-term hormones with mainly local effects as prednisone acetate was safer than long-term hormone with more systemic impact, such as dexamethasone and triamcinolone acetonide.
In epidural steroid injection, there is a rare, potentially, even serious complications of the nervous system, the surrounding tissue, organs and other systems, etc., such as brain and spinal cord infarct, epidural hematoma, disc space infection, menstrual disorders, allergies and so on. The mechanism of some complications remains unclear and needs further study. Faced with the above factors of insecurity, we should develop a standard and reasonable operating procedures to guide the clinical application as soon as possible. Concerned about basic research of the epidural injection in the later practice of scientific research. And use of a unified, standard treatment monitoring indicators and time of assessment endpoints in future clinical trials, with long-term observation of the clinical response to the relevant factors, and comparing the effect of the difference between the different groups. It is recommended that multiple clinical centers together to study, collection of valid data to evidence-medical analysis, using the scientific conclusions to guide the clinical application.
4.2Epidural injection of high concentrations of prednisone has a negative impact on glucose, lipids, and made the pathological changes of similar necrosis on the femoral head. Therefore, we should strictly control indications of epidural steroid injection in treatment of pain-related diseases. For patients with diabetes, obesity or hyperlipemia, as well as severe osteoporosis, mainly relying on the unilateral femoral head to load, with more concentrated stress should be used with caution in epidural steroid therapy, and prohibited to multiple injections. In other patients with repeated epidural injection, should pay attention to the routine monitoring of blood glucose, blood lipids, platelets and plasma viscosity, as convenient indicators of important reference value for the prevention and treatment of femoral head necrosis. Concerned about the results of the present study, the less low concentrations of steroid using in the epidural space is a much safer choice.
4.3In alkaline solution group, and the routine epidural injection liquid of normal control group, the nerve root function did not occur significantly sensitive or slow changes, and there was not obvious histological damage of nerve root before and after experiment. Showed that drug composition of the experimental group and control group did not cause significant damage to nerve root function and histology, which was a relatively safe drug of choice. Namely the alkaline solution of caudal injection will not cause the harmful effects of nerve root function and histology, this formula can be used as a safe choice. However, due to long-term hormone maybe easily leading to sodium and water retention, if we join the alkalization of the solution will more easily lead to balance disorders in electrolyte and acid-base of the body, causing sodium and water retention or aggravating circumstances. Taking into account the existence of the risk of sodium and water retention, I believe that by reducing the current clinical practical dosage of5%bicarbonate5ml can reduce the occurrence of such risks. As for the ideal amount, we need further basic experimental and clinical research as guidance, in order to better play its clinical value under the premise of safety.
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