低钠血症 Hyponatremia 朱大龙南京大学医学院附属鼓楼医院水、钠代谢的调节定 义血清钠135mmol/L为低钠血症； 仅反映钠在血浆中浓度的降低，并不一定表示体内总钠量的丧失，总体钠可以正常甚或稍有增加。临床上极为常见，特别在老年人中。主要病症为软弱乏力、恶心呕吐、头痛思睡、肌肉痛性痉挛、神经精神病症和可逆性共济失调等。分类根据渗透压低渗性低钠血症等渗型低钠血症高渗性低钠血症根据低钠血症发生时的血容量变化低血容量性低钠血症 失钠多于失水。 血容量正常性低钠血症 总体水增加而总钠不变。 高血容量的低钠血症 总体水增高大于血钠升高根据血钠降低的程度可分为 重度低钠血症120mmol/L中度低钠血症130mmol/L轻度低钠血症135mmol/L 此外还有假性低钠血症，见于明显的高脂血症和高蛋白血症。病 因假性低钠血症渗透压正常假性低钠血症渗透压正常高脂血症、高蛋白血症显著升高高脂血症、高蛋白血症显著升高高渗透性性低钠血症高血糖、甘露醇或甘油治疗高渗透性性低钠血症高血糖、甘露醇或甘油治疗低血容量性低钠血症低血容量性低钠血症胃肠道消化液丧失如呕吐、腹泻、胰腺炎及胰腺造瘘和胃肠道消化液丧失如呕吐、腹泻、胰腺炎及胰腺造瘘和胆瘘等；胆瘘等； 皮肤水盐丧失大量出汗、大面积三度烧伤、胰腺纤维性皮肤水盐丧失大量出汗、大面积三度烧伤、胰腺纤维性囊肿囊肿体腔转移丧失体腔转移丧失 小肠梗阻、腹膜炎、急性静脉阻塞、严重小肠梗阻、腹膜炎、急性静脉阻塞、严重烧伤等烧伤等肾性失钠慢性肾脏疾病、失盐性肾病、盐皮质功能减退、肾性失钠慢性肾脏疾病、失盐性肾病、盐皮质功能减退、SIADH、糖尿病酮症酸中毒、利尿剂、糖尿病酮症酸中毒、利尿剂脑性盐耗损综合征下视丘脑或脑干损伤引起脑性盐耗损综合征下视丘脑或脑干损伤引起血容量正常性低钠血症血容量正常性低钠血症SIADH糖皮质激素缺乏肾病综合症不适当利尿精神性多饮甲状腺功能减退症严重慢性肺部疾病、恶液质、营养不良高血容量性低钠血症高血容量性低钠血症充血性心力衰竭肝功能衰竭慢性肾功能衰竭肾病综合征SIADH恶性肿瘤肺燕麦细胞癌、前列腺癌、胸腺癌、淋巴瘤等肺部纵膈疾病- 肺炎、曲霉病、脓肿、TB, PPV中枢神经系统疾病 脓肿、创伤、脑膜炎、中风、SAH内分泌疾病 Addison病、甲减手术后急性间歇性卟啉症 药物性SSRI、苯丙胺相关药、长春新碱、环磷酰胺，卡马西平，溴隐亭NSAIDS：通过降低肾脏的前列腺素低血容量性低钠血症一低血容量性低钠血症二正常容量或高容量性低钠血症一正常容量或高容量性低钠血症二病理生理病理生理 低钠血症从病因来说，不外是钠的丧失和耗损，或者是总体水相对增多，总的效应是血浆渗透压降低(血钠浓度是血浆渗透压维系的主要成分)。失钠又常伴有失水，不管低钠血症的病因为何，有效血容量均缩减，从而引起非渗透压性ADH释放，以图增加肾小管对水的重吸收，以免血容量进一步缩减。然而这种保护机制更加重了血钠和血浆渗透压的降低，这种代偿机制发生于有效血容量缩减的早期，当血Na+下降到135mmol/L时，ADH释放那么被抑制。 正常时细胞内渗透压保持稳态平衡。当血浆钠浓度降低，细胞外液渗透压下降，细胞外水流血细胞内，使细胞肿胀，以致细胞功能受损甚至破坏，其中以脑细胞肿胀，可导致低钠血症最严重的临床表现。血容量缩减如果得不到纠正，那么可使血压下降，肾血流量减少，肾小球滤过率降低，可导致肾前性氮质血症。 临床表现低钠血症的临床表现严重程度取决于血钠水平和血钠下降的速率。血钠在125mmol/L以上时，极少引起病症；钠在125130mmol/L之间时，也只有胃肠道病症。此时主要病症为软弱乏力、恶心呕吐、头痛思睡、肌肉痛性痉挛、神经精神病症和可逆性共济失调等。脑水肿临床表现有抽搐、木僵、昏迷和颅内压升高病症，严重可出现脑幕疝。如果低钠血症在48h内发生，那么有很大危险，可导致永久性神经系统受损的后果。慢性低钠血症者，那么有发生渗透性脱髓鞘的危险，特别在纠正低钠血症过分或过快时易于发生。除脑细胞水肿和颅高压临床表现外，由于血容量缩减，可出现血压低、脉细速和循环衰竭，同时有失水的体征。总体钠正常的低钠血症那么无脑水肿临床表现。实验室检查血生化及电解质测定血浆渗透压测定 尿渗透压测定 血BNP测定点尿钠浓度测定 血尿酸水平渗透压血浆渗透压血浆渗透压Posm)Posm = 2 (Na+K) +血糖血糖+血尿素氮血尿素氮正常正常 = 2 (140) + 5 + 5 = 290 (275-290 mM) 尿渗透压尿渗透压UOSM :正常正常: 400-500 mM最大稀释最大稀释 50-100 mM (USG 1.002-1.003)最大浓缩最大浓缩 900-1200 mM (USG 1.030-1.040)浓缩尿浓缩尿: 500 mM (至少至少!), USG UOSM POSM is not enough to R/O Diabetes Insipidus诊 断确定是否为真正的低钠血症血浆渗透压Posm 正常范围 280-295mOsm/kg如果 295 mOsm/kg高血糖或甘露醇的使用高渗性低钠血症如果在280-295 mOsm/kg之间 :假性低钠血症：高脂血症或高蛋白血症如果280 mOsm/kg评价容量状态血浆渗透压 280 mOsm/kg高容量性:充血性心力衰竭、肝硬化、肾病综合症、急慢性肾功能衰竭正常容量性： SIADH、甲减、精神性多饮、肾病综合症不适当利尿、嗜啤酒狂、手术后、钠摄入缺乏、极低蛋白饮食等低容量性胃肠消化液丧失、皮肤出汗、利尿剂使用、脑盐耗综合症、体腔转移丧失、盐皮质激素缺乏Addison病低钠血症的诊断思路 低钠血症的治疗应根据病因、低钠血症的类型、低钠血症发生的急慢及伴随疾病而采取不同处理方法，故强调低钠血症的治疗应个别化，但总的治疗措施包括： 去除病因； 纠正低钠血症； 对症处理； 治疗合并症。 治 疗低钠血症的纠正速度24小时内升高小时内升高10-12mmol/L，48小时内血钠升高小时内血钠升高18 mmol/L治 疗急性低钠血症急性低钠血症 =脑水肿、脑疝脑水肿、脑疝方法方法:去除病因去除病因病症轻到中度病症轻到中度:无需进一步干预治疗；无需进一步干预治疗；严重病症严重病症:高渗盐水输注高渗盐水输注(3%) 3% NaCl检测输液速度检测输液速度-防止中枢脑桥脱髓鞘病变防止中枢脑桥脱髓鞘病变检测血钠水平检测血钠水平 q2h24小时内升高小时内升高10-12mmol/L，48小时内小时内血钠升高血钠升高18 mmol/LVerbalis, Joseph G., Stephen R. Goldsmith, Arthur Greenberg, Robert W. Schrier, and Richard H. Sterns. Hyponatremia Treatment Guidelines 2007: Expert Panel Recommendations. The American Journal of Medicine 120 (2007): S1-S21.治 疗慢性低钠血症慢性低钠血症 = 脑适应脑适应重要是控制低钠血症的纠正速度重要是控制低钠血症的纠正速度 脑适应脑适应性、细胞内溶质外溢性、细胞内溶质外溢血钠纠正过快，大脑容易受损伤血钠纠正过快，大脑容易受损伤由于脑由于脑细胞不能重新摄取溶质，细胞萎缩细胞不能重新摄取溶质，细胞萎缩“中枢脑桥髓鞘溶解中枢脑桥髓鞘溶解 / “渗透性脱髓鞘渗透性脱髓鞘作用作用 大脑局限在颅内，大脑局限在颅内，构音困难、吞咽困难、癫痫、神智改变、构音困难、吞咽困难、癫痫、神智改变、四肢轻瘫、低血压四肢轻瘫、低血压1-3天内纠正低钠血症天内纠正低钠血症24小时内升高小时内升高10-12mmol/L，48小时内血小时内血钠升高钠升高/= 4mEq/L :Conivaptan 40mg/day: 24 hoursConivaptan 80mg/day: 10 hoursPBO: no increase within 4 day infusionChange in serum Na from baseline to end of treatmentConivaptan 40mg/day: 6.3 mEq/LConivaptan 80mg/day: 9.4 mEq/LPBO: 0.8 mEq/LPatients with increase in Na /=6mEq/L or Na /=135 mEq/LConivaptan 40mg/day: 69% (6.3)Conivaptan 80mg/day: 88.5% (23)PBO: 20.7% (6)Change in serum Na from Baseline to 6-9days post treatment :Conivaptan 40mg/day: 8.1mEq/L (n=13)Conivaptan 80mg/day: 4.7 mEq/L (n=26)PBO: 5.2 mEq/L (n=17)Assessment of the Efficacy and Safety of Intravenous Conivaptan in Euvolemic and Hypervolemic HyponatremianDiscontinuation was mainly due to Infusion site reactionsnOther ADRs: hypotension, postural hypotension, pyrexia, hyperkalemia, infusion site thrombosisProspective, multi-center, randomized centrally, double-blind, placebo controlledConducted 2 trials to assess reproducibility (SALT-1 & SALT-2)Tolvaptan 15mg tab 1 tab PO Daily x 30 days OR PBOImportant Patient Population Criteria:InclusionEtiologies: CHF, cirrhosis or SIADHExclusion Criteria:Other etiologiesHypovolemic hyponatremiaOther cardiac diseases (post-MI, SVT, SBP90)Serum Na 120 mmol/L w/ neurological impairmentPoor prognosis not tolerating fluid shifts: short-term survivalTolvaptan, a Selective Oral Vasopressin V2-Receptor Antagonist, for HyponatremiaNew England Journal of Medicine 355 (2006): 2099-112Similar Baseline Characteristics across study groups (except height in SALT-2), Mean baseline Na: 128 mEq/LCo-Administration/Co-intervention: Fluid restriction was not mandatory; treatment with other agents were not allowed (demeclocycline, lithium, urea)Dose adjustments were made at the discretion of the investigator at Day 4 Drug was administered until day 30, final assessments done at day 37nValues were statistically significantnIncreases in Na were greater in Tolvaptan group than PBO in both trials and in both stratifications at Day 4 and much more at Day 30nIncreases were more rapid (by day 4) and greater (marked hyponatremia)New England Journal of Medicine 355 (2006): 2099-112.Tolvaptan patients reached normal Na levels on day 4 and 30 more than PBODay 4: SALT-1 (40% vs 13%) SALT-2 (55% vs11%) Day 30: SALT-1 (53% vs 25%) SALT-2 (58% vs25%) Less “marked hyponatremia Day 4: SALT-1 (13% vs 49%) SALT-2 (10% vs 40%) Day 30: SALT-1 (7% vs 35%) SALT-2 (15% vs 32%) not sigSF-12 scoresShowed difference in “mental component summary in “marked hyponatremia patients, but not overallVitality, social functioning, calmness, sadnessNo difference in physical component summaryOTHER:Day 37 analysis: Na concentrations showed no difference between each armTolvaptan (Samsca) Tolvaptan, a Selective Oral Vasopressin V2-Receptor Antagonist, for Hyponatremia. New England Journal of Medicine 355 (2006): 2099-112.ADRMost common: Thirst (14%;5%); Dry mouth (13%;4%)Incidence: Tolvaptan: 171 patients PBO: 176, not all ADRs were deemed to be related to study drugweakness, nausea, constipation, peripheral edema, ascites, diarrhea, fatigue, vomitingTolvaptan: 8 patients withdrew due to ADR Rash, dysguesia, nocturia, urinary frequency, exanthema, muscle weakness, hypernatremiaPBO: 8 patients withdrew due to ADR Rash, ARF, increased SCr, decreased Na, aggravated hyponatremia, vomitingCompleted Follow-up 7-days & 30-days:Tolvaptan: N=171 (76%)PBO: N=154 (69%)Study Withdrawal:Total: N= 123 Tolvaptan: 54 (24%)PBO: 69 (31%)Tolvaptan (Samsca) Tolvaptan, a Selective Oral Vasopressin V2-Receptor Antagonist, for Hyponatremia. Schrier, Robert G., Peter Gross, Mihai Gheorghiade, Tomas Berl, Joseph G. Verbalis, Frank Czerwiec, and Cesare Orlandi. Tolvaptan, a Selective Oral Vasopressin V2-Receptor Antagonist, for Hyponatremia. New England Journal of Medicine 355 (2006): 2099-112.Conivaptan VS Tolvaptan