输入新鲜冰冻血浆治疗颈脊髓损伤后低钠血症

doi:10.3969/j.issn.2095-4344.2013.17.024

摘要/Abstract

摘要：

背景：课题组考虑到新鲜冰冻血浆在临床上有综合治疗的价值，如抗休克、免疫、止血和解毒等，并能纠正胶体渗透压。如果在限水、补钠的同时补充新鲜冰冻血浆能提高脊髓损伤患者血钠水平，将为临床治疗脊髓损伤后低钠血症找到一个新的突破点。
目的：建立家兔颈脊髓损伤并发低钠血症动物模型，观察输入新鲜冰冻血浆治疗颈脊髓损伤并发低钠血症的疗效。
方法：健康成年家兔60只，采用改良ALLen氏打击法制作家兔颈脊髓损伤模型，将幸存且合并低钠血症的40只家兔随机分为2组，对照组20只，实验组20只，再按取标本时间不同依次分为1，3，6，10，15 d组，共10组，每组4只。实验组家兔出现低钠血症后每24 h静脉输入20 mL新鲜冰冻血浆(即1 d组输入1次，3 d组输入3次，6 d组输入6次，10 d组输入10次，15 d组输入15次)。对照组家兔每24 h静脉输入20 mL生理盐水。各组动物分别于术前及输入血浆后24 h采取标本分别进行血清钠离子及脊髓组织钠离子测定。
结果与结论：①术后3 d和术后6 d时实验组及对照组家兔的平均血钠浓度较术前明显降低(P < 0.05)。术后10，15 d时实验组血钠浓度升高，而对照组血钠水平持续下降，与实验组血钠水平比较差异有显著性意义(P < 0.05)。②术后3，6 d时实验组及对照组家兔脊髓组织钠浓度较空白对照组明显升高(P < 0.05)。实验组输入血浆10 d后脊髓组织钠浓度逐渐恢复，而对照组脊髓组织钠浓度持续升高，与实验组脊髓组织钠浓度比较差异有显著性意义(P < 0.05)。结果可见颈脊髓损伤后易并发低钠血症，输入新鲜冰冻血浆对颈脊髓损伤并发低钠血症的纠正有一定作用。

关键词: 骨关节植入物, 脊柱损伤基础实验, 低钠血症, 脊髓损伤, 新鲜冰冻血浆, 家兔, 模型, 治疗, 血钠浓度, 神经损伤, 纠正, 脊髓

Abstract:

BACKGROUND: Studies have shown that fresh frozen plasma has comprehensive treatment value in clinic, such as anti-shock, immunology, hemostasis and detoxification, and it can correct the colloid osmotic pressure. Complementing the fresh frozen plasma during water limitation and sodium supplement can increase the sodium levels in patients with spinal cord injury, which provide a new breakthrough for hyponatremia after clinical treatment of spinal cord injury.
OBJECTIVE: To establish a rabbit model of cervical spinal cord injury combined with hyponatremia, and to observe the effectiveness of fresh frozen plasma transfusion for hyponatremia after cervical spinal cord injury.
METHODS: Sixty healthy adult rabbits subjected a Allen’s punch method to establish rabbit models of cervical spinal cord injury. Forty survived and hyponatremia rabbits were randomly divided into two groups: control group and experimental group, 20 rabbits in each group, and then each group was divided into 1, 3, 6, 10 and 15 days group according to time for taking the specimens, a total of 10 sub-groups and 4 rabbits in each sub-group. The rabbits in the experimental group were injected with 20 mL fresh frozen plasma at 24 hours after hyponatremia appeared (1 day group was injected for one time, 3 days sub-group was injected for three times, 6 days sub-group was injected for six times, 10 days sub-group was injected for 10 times and the 15 days sub-group was injected for 15 times). The rabbits in the control group were injected with 20 mL normal saline every 24 hours. The specimens in each group were taken before operation and 24 hours after fresh frozen plasma transfusion to detect the sodium ions in the plasma and spinal tissue.
RESULTS AND CONCLUSION: Sodium concentration in plasma and spinal cord of the control group and experimental group at 3 and 6 days after operation was significantly decreased when compared with that before operation (P < 0.05). Sodium concentration in plasma and spinal cord of the experimental group at 10 and
15 days after operation was increased, while the control group was decreased continuously, and there was significant difference of sodium concentration between control group and experimental group (P < 0.05). Sodium concentration in the spinal cord of the control group and experimental group at 3 and 6 days after operation was significantly increased when compared with that of the blank control group (P < 0.05). Sodium concentration in the spinal cord of the experimental group was returned to normal level after fresh frozen plasma injected for 10 days, while the sodium concentration of the control group was increased continuously, there was significant difference of sodium concentration in the spinal cord between the control group and the experimental group (P < 0.05). Hyponatremia is a common complication after cervical spinal cord injury. Fresh frozen plasma transfusion is a good way to treat hyponatremia after acute cervical spinal cord injury.

Key words: bone and joint implants, basic experiment of spinal injury, hyponatremia, spinal cord injury, fresh frozen plasma, rabbit, model, treatment, sodium concentration, nerve injury, correction, spinal cord

中图分类号:

R318

张圣飞，王永祥，冯新民，陶玉平. 输入新鲜冰冻血浆治疗颈脊髓损伤后低钠血症[J]. 中国组织工程研究, 2013, 17(17): 3223-3230.

Zhang Sheng-fei, Wang Yong-xiang, Feng Xin-min, Tao Yu-ping. Fresh frozen plasma transfusion for the treatment of hyponatremia after cervical spinal cord injury[J]. Chinese Journal of Tissue Engineering Research, 2013, 17(17): 3223-3230.

图/表（结果） 4

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引言

材料方法

设计：随机对照动物实验。

时间及地点：实验于2011年3至12月在扬州医学院中心实验室完成。

材料：

实验动物：清洁级健康成年家兔60只，雌雄不限，体质量2.5-3.0 kg，由扬州医学院中心实验室提供，动物质量合格证号:SCXK20120007。实验过程中对动物的处置符合2009年《Ethical issues in animal experimentation》相关动物伦理学标准的条例。

测量脊髓损伤后低钠血症患者血清钠离子浓度及脊髓组织钠离子浓度所需的主要仪器：

Main reagents and instruments:

实验方法：

脊髓损伤动物模型的制备^[14-16]：采用改良ALLen氏打击法制作家兔脊髓损伤动物模型，撞击成功标准为：损伤处脊髓外观出血、水肿，家兔尾巴出现来回摆动，四肢软瘫。家兔脊髓损伤模型筛选要求：四肢肌力0级，BBB评分0分。

家兔麻醉后俯卧于手术台上，以C₅棘突为中心作切口，切除棘突及椎板，暴露脊髓，Allen氏法垂直撞击脊髓，10 g打击器经脊髓背侧自垂直高度10 cm坠落打击脊髓。止血后关闭切口。术后实施经胃皮区胃造瘘术^[17-20]。

动物分组：术后经胃造瘘管瑞素肠内营养乳剂喂养家兔，每日瑞素肠内营养乳剂量为200 mL，将幸存且合并低钠血症(血清钠离子浓度低于135 mmol/L)40只家兔随机分为对照组20只，实验组20只，再按取标本时间不同依次分为1，3，6，10，15 d组，共10组，每组4只。另设立一空白对照组4只：未进行手术干预，仅行血钠及脊髓组织钠离子测定。

异体空白血浆制备及血浆输入：①空白血浆制备：家兔麻醉后，经颈总动脉插管取血约50 mL，放入肝素化的离心管中，离心10 min(3 000 r/min)，分离血浆约10 mL，放入-50 ℃速冻，成形后放置-30 ℃冰箱备用。使用前取出放于30-37 ℃水浴溶化后尽快输入。②血浆输入：实验组家兔出现低钠血症后每24 h经耳缘静脉输入 20 mL血浆(即1 d组输入1次，3 d组输入3次，6 d组输入6次，10 d组输入10次，15 d组输入15次)，每次在半个小时内输液完毕。对照组家兔每24 h经耳缘静脉输入20 mL生理盐水(即1 d组输入1次，3 d组输入3次，6 d组输入6次，10 d组输入10次，15 d组输入15次)。

标本采集及结果检测：①各组动物分别于术前及输入血浆后24 h采取标本，血液标本经耳缘静脉采取，约 3 mL，应用血液生化分析仪(Chiron 348；Chiron Diagnostics Corp；MA，USA)进行血钠测定。②参考Happel法^[4]，各组动物分别于术前及输入血浆后24 h处死家兔取脊髓标本(约1个椎体高度脊髓组织)并应用WYX-402型原子分光光度计测量脊髓组织钠离子浓度，测量时稀释200倍。

主要观察指标：血清钠离子浓度及脊髓组织钠离子浓度。

统计学分析：采用SPSS 17.0统计软件进行分析，统计数据以x(_)±s表示，各项指标组间比较采用多个样本均数比较的方差分析，以P < 0.05为差异有显著性意义。

讨论

低钠血症是颈脊髓损伤患者早期常见的但容易被忽视的严重并发症。创伤性脊髓损伤患者尤其是高位颈脊髓损伤者，急性期易并发低钠血症，其发生率甚至高达45%-100%^[21-24]，60只家兔建立颈脊髓损伤模型后40只存活且并发低钠血症，发生率达66.7%。由于低钠血症症状与创伤引起的症状相重叠，临床上难以观察，多在常规检查中发现。如果治疗不当，低钠血症难以纠正，且可加重脊髓损伤或使已经恢复的神经功能再次丧失，严重的低钠血症可造成患者永久性神经损伤、昏迷甚至死亡。

关于低钠血症发生的时间文献报道不一^[25-27]，一般认为从颈髓损伤到出现低钠血症的时间为6.4-8.9 d。颈髓损伤至血钠降低至最低水平的时间为8.7-17.3 d，血钠降至最低到血钠开始回升的时间为(21.8±10.2) d，患者出现低钠血症至低钠血症消失的时间为(30.4±6.0) d。实验组中输入血浆量20 mL，目前无文献或实验方面根据，主要是根据临床上少量多次原则每日予200-300 mL血浆，按公斤体质量算约5 mL/kg，实验中适当加量。

目前对脊髓损伤后并发低钠血症的机制尚不完全了解，学术界对此长期存在争论，尚无一个确定性理论合理的解释这一临床现象。多数认为与血液循环中抗利尿激素水平升高有关。一般认为本病属中枢性低钠血症范畴，是尿稀释功能受损后，表现为逐渐加重的低血钠、高尿钠综合征，包括脑性耗盐综合征^[28-31]和抗利尿激素分泌异常综合征^[32-37]，是渗透压调节中枢功能紊乱而导致低钠血症^[38]。抗利尿激素分泌异常综合征主要由神经系统损伤致抗利尿激素分泌与血浆渗透压不相协调，抗利尿激素释放增多，水潴留、尿钠排出增多引起；脑性耗盐综合征主要由脑损伤和颅内疾病致心钠素和脑钠素分泌增多，产生利钠利尿作用而引起。张立等^[39]报道急性完全性颈脊髓损伤后低钠血症患者抗利尿激素水平减低，且均排除了颅脑损伤^[40-42]，因此抗利尿激素分泌异常综合征和脑性耗盐综合征难以完全解释其发病机制。

目前认为导致脊髓损伤后低钠血症的主要病理机制包括^[43-47]：①颈髓横断后，全身血管失去交感神经支配，出现血管舒张，周围血管阻力降低，循环量减少，引起抗利尿激素分泌减少，最终出现多尿。②心房尿钠排泄物浓度变化可能参与尿钠排泄导致低钠血症。③低血容量、外科手术等非渗透性调节机制引起抗利尿激素水平升高，使体内在低渗和低钠状态也不能排出过多的水负荷。④急性脊髓损伤后交感神经抑制使正常排钠节律被扰乱，致尿钠排出过多。⑤低钠摄入引起的延迟性保钠反应。

王鹤等^[48]探讨急性颈脊髓损伤患者并发低钠血症的病因、发病机制和治疗方法，收治严重创伤导致急性颈脊髓损伤伴高位截瘫并发低钠血症患者57例，男46例，女11例；年龄26-69岁，平均39.5岁；颈椎骨折或脱位55例，无骨折或脱位型脊髓损伤2例；完全性损伤28例，不完全性损伤29例。神经功能损害按ASIA分级：A级28例，B级25例，C级4例。每日监测心率、血压、尿量、血钠，诊断低钠血症后即开始静脉补液、补钠，每隔2 d检测尿钠、血浆渗透压、尿渗透压，根据监测结果及治疗反应判断低钠原因是由脑性盐耗综合征还是由抗利尿激素不适当分泌综合征引起，前者继续静脉补液、补钠，后者严格限水同时静脉补钠直至低钠纠正。结果57例中诊断脑性盐耗综合征者42例，抗利尿激素不适当分泌综合征者15例。治疗3周后所有患者的心率、血钠、血渗透压有明显回升(P < 0.01)，血压、尿渗透压升高，尿钠减少(P均 < 0.05)，尿量未见明显减少(P > 0.05)。出院时与治疗3周比较，心率、血浆渗透压、尿渗透压进一步回升，尿量减少，尿钠进一步减少(P < 0.05)，血压无明显改变(P > 0.05)，结果说明急性颈脊髓损伤后并发低钠血症受多因素影响，发病机制主要为脑性盐耗综合征及抗利尿激素不适当分泌综合征，治疗时应注意鉴别，根据不同病因采取补液或限液治疗。

研究发现创伤性脊髓损伤患者出现低钠血症发生率及程度与脊髓损伤的平面有关，也与脊髓损伤的程度有关。并发低钠血症的患者中，脊髓损伤的平面越高，低钠血症的发生率也越高^[49-52]，这可能是由于脊髓损伤的平面越高，其发生中枢性低钠血症的可能性和危险性也就越高的缘故。同时同一节段中完全性损伤的患者多于不全性损伤的患者。另有研究表明颈髓损伤的严重程度与低钠血症的发生及程度有着明显的相关性，颈髓损伤越严重，其低钠血症的发生率越高，且程度也越重。

刘伟等^[53]回顾性总结急性颈脊髓损伤后低钠血症的发生特点，并分析其可能的发生原因，以及脊髓损伤严重程度、性别、年龄等因素对血钠变化的影响。共入选病例102例，男83例，女19例；年龄17-68岁，平均45.6岁。完全性脊髓损伤组23例，不完全性脊髓损伤组60例，无神经功能障碍组19例。共发生低钠血症共39例，完全性脊髓损伤组15例(65%)，不完全性脊髓损伤组23例(38%)，无神经功能障碍组1例(5%)，低钠血症发生率在3组间两两比较，差异有显著性意义，完全性脊髓损伤组低钠血症的发生率明显高于不完全性脊髓损伤组和无神经功能障碍组。Logistic逐步回归分析结果显示低钠血症与患者脊髓损伤程度有明确相关关系，而与患者的年龄、性别、脊髓损伤节段无相关关系。结果说明急性颈脊髓损伤后具有较高的低钠血症发生率，虽然影响钠盐平衡的因素及相互作用非常复杂，但颈脊髓损伤致自主神经功能障碍、神经内分泌功能异常以及血液动力学改变可能是导致颈脊髓损伤后电解质系统异常的重要原因。唐健等^[54]采用单因素分析表明颈髓损伤严重程度、是否合并脑损伤、是否使用呼吸机、是否合并感染对低钠血症是否发生具有显著影响。Logistic多元回归分析表明颈髓损伤严重程度、是否使用呼吸机、是否合并感染对低钠血症发生具有显著影响，得出如下结论：对于急性颈髓损伤后低钠血症患者，其颈髓损伤的严重程度是发生低钠血症的重要影响因素，而是否使用呼吸机、是否合并感染对发生低钠血症的影响可视为与损伤严重程度相关。

急性脊髓损伤患者发生低钠血症时除了积极治疗原发疾病、减弱或消除低钠血症的影响因素以外，还应及时判断引起低钠血症的原因，并根据不同的病因作出相对应的处理，低钠血症常反复发生，这可能与基础疾病未治愈有关。在患者首次低钠血症被纠正后，在治疗原发病时努力避免产生医源性低钠血症，如避免长期不适当使用利尿剂，避免过分限制钠盐摄入，避免大量使用葡萄糖液做药物溶剂。

一般情况临床医生治疗低钠血症并不困难，但对于创伤性脊髓损伤并发低钠血症的患者，尤其是重度低钠血症的患者，临床上治疗过程中病情顽固、反复，常使临床医生感到十分棘手。脊髓损伤后并发轻、中度低钠血症，及时发现及时治疗，不会发生严重后果。但如果血钠降低较快，或<120 mmol/L，出现重度低钠血症，则纠正起来非常困难，常是造成脊髓损伤患者早期死亡的原因之一。对于创伤性脊髓损伤，尤其高位颈脊髓完全损伤患者应密切注意血钠水平，有条件时还应注意监测尿钠水平。患者入院后立即行生化指标检查，一旦出现低钠血症，应每日复查血钠水平，同时注意观察患者精神状态，神经系统体征变化，适度限水，合理饮食，调整利尿剂用量，适当增加口服钠盐，严重者静脉补充高渗盐水等手段，但对中、重度低钠血症者难以收到明显效果。针对每个患者的临床表现鉴别何种机制占主要因素并针对性预防和治疗是治疗颈髓损伤后低钠血症的关键。孙嗣国等^[55]回顾性分析解放军第四军医大学唐都医院骨科收治的187例资料完整的急性颈髓损伤患者的资料，低钠血症发生率为60.42%；四肢完全瘫痪患者低钠血症发病率高于四肢不完全瘫痪的患者(77.36% vs. 38.27%，P < 0.01)，限制液体摄入量、适量补钠可使大部分患者血钠于一两周逐渐恢复正常，少数患者需要增加补液量及补钠量，血钠经三四周后恢复正常，尽早补充胶体液有助于低钠血症的纠正。

实验结果表明损伤后脊髓组织中钠离子含量升高，内皮素通过促进靶细胞膜上的Na⁺/H⁺交换，促进钠离子内流，增加细胞内钠离子浓度。细胞内外钠离子平衡的紊乱导致细胞水肿和功能紊乱。细胞水肿可使细胞内压增高，从而引起微循环障碍，组织缺血、缺氧进一步加重，最终导致胞溶解。钠离子含量的改变还会影响神经电位，使神经系统产生、传导兴奋的功能紊乱，导致中枢神经的进一步损害。

研究表明，新鲜冰冻血浆在临床上有综合治疗的价值^[7]，如抗休克、免疫、止血和解毒等，并能纠正胶体渗透压。补充新鲜冰冻血浆后再次发生低钠血症的时间延长，机体内环境的稳定依赖于机体的调节机制，当疾病等因素破坏了机体的调节机制，便会发生水、电解质等失调，称内环境紊乱综合征。有报道称低钠血症与血浆激素有相关性，即血清钠浓度与血浆肾素、血管紧张素和心钠素呈明显负相关，故推测新鲜冰冻血浆中含有某种因子^[56-57]，其对维持血清钠浓度正常有一定作用，该因子可能为脊髓损伤后合并低钠血症患者所缺乏，故补充新鲜冰冻血浆可能提供了该因子，稳定了机体调节机制，其具体机制未明，但对于脊髓损伤后合并低钠血症患者补充新鲜冰冻血浆不失为维持电解质稳定的一种较好方法。