欧洲低钠血症诊疗指南

1、 2014 欧洲低钠血症诊疗指南解读 欧洲危重病学会（ESICM）， 欧洲内分泌学会（ESE） 欧洲肾脏最佳临床实践（European Renal Best Practice ERBP)为代表的欧洲肾脏病协会和欧洲透析与移植协会（ERA-EDTA）共同制定了欧洲低钠血症临床诊疗指南 低钠血症 Hyponatraemia, defined as a serum sodium concentration135 mmol/l, is the most common disorder of body fluid and electrolyte balance encountered in clinic

2、al practice. It occurs in up to 30% of hospitalised patients and can lead to a wide spectrum of clinical symptoms, from subtle to severe or even life threatening (10, 11) 定义： 血清钠低于135mmol/L 临床最常见的水盐失衡，其发生率约占住院患者的30% 症状不一，从轻微到致命 In most cases, hyponatraemia reflects low effective osmolality or hypoto

3、nicity, which causes symptoms of cellular oedema. However, hyponatraemia may also (rarely) occur with isotonic or hypertonic serum if the serum contains many additional osmoles, such as glucose or mannitol. Therefore, we discuss not only how hypo-osmolar but also how isosmolar and hyperosmolar state

4、s develop. 绝大多数情况下，低钠血症反映了低有效渗透压状态，主要引起细胞水肿 然而，如果血清含有其他渗透性物质如葡萄糖和甘露醇，则低钠血症在个别情况下也可发生于等渗或高渗情况。 因此，低钠血症不仅见于低渗，也见于等渗和高渗的情况。 Severe symptoms of hyponatraemia are caused by brain oedema and increased intracranial pressure. Brain cells start to swell when water moves from the extracellular to the intracel

5、lular compartment because of a difference in effective osmolality between brain and plasma. patients with chronic hyponatraemia and no apparent symptoms can have subtle clinical abnormalities when analysed in more detail. Such abnormalities include gait disturbances, falls, concentration and cogniti

6、ve deficits patients with chronic hyponatraemia more often have osteoporosis and more frequently sustain bone fractures than normonatraemic persons 低钠血症严重症状为脑水肿。 低渗的血浆向高渗的脑细胞进行水转移，导致细胞肿胀 慢性和无明显症状的低钠血症患者，可有如下轻微症状：步态不稳，跌倒，注意力不集中和认知障碍 慢性低钠血症患者更易发生骨质疏松和骨折图示：大脑对低钠血症的适应过程：1即可反应2快速适应3慢适应调节4不适当纠正（快速升高渗透压）5适

7、当纠正（缓慢提高渗透压） 6. 低钠血症诊断Diagnosis of hyponatraemia6.1. 分类：Classification of hyponatraemia 根据血钠浓度分类： 6111： 轻度(mild)低钠血症：血钠： 130135mmol/l 6112： 中度（moderate）低钠血症：血钠： 125129mmol/l 6113： 重度（profound）低钠血症： 血钠： 125mmol/l 依据发生时间分类： 61216121： 急性低钠血症48h100mOsm/kg 尿渗透压急性或严重症状？100mOsm/kg:原发性烦渴盐摄入不足、嗜酒30mmolYN有效动脉

8、血容量不足考虑：利尿剂肾脏疾病如果ECF减少：呕吐，肾耗盐，脑耗盐隐匿性利尿，原发性肾上腺功能不全如果ECF正常:SIAD,甲减，隐匿性利尿继发性肾上腺功能不全如果ECF减少：呕吐，第三腔室，远程利尿剂如果ECF增加：心衰，肝硬化，肾病综合征其他疾病Y立即开始低钠血症治疗N低钠血症诊断程序图示 A urine osmolality 100 mOsm/kg should trigger additional diagnostic testing to determine the underlying cause of hyponatraemia: ultimately classified in

9、to hyponatraemia with increased, normal or redu extracellular fluid volume. Because clinical assessment of fluid status is often difficult and may lead clinicians down the wrong path, we have consciously steered away from the traditional approach of including it in the algorithm here. Instead, we re

10、commend determining urine sodium concentration on a spot urine sample. It is important to collect the serum and urine sample around the same time to allow correct interpretation of the values. We have selected a urine sodium concentration threshold of 30 mmol/l because several studies indicated good

11、 sensitivity and acceptable specificity in distinguishing hypovolaemia from euvolaemia or hypervolaemia (89, 103, 107, 108). This means that a urine sodium concentration 30 mmol/l suggests low effective arterial blood volume, even in patients on diuretics. 尿渗透压100 mOsm/kg 时，应进一步明确低钠血症的原因，最终将其分为高、正常，

12、低细胞外液容量低钠血症。 由于临床常常难于评价液体状况，致使医生做出错误判断。指南推荐检查尿钠含量。应同时采集血液和尿液标本进行检测。 指南选择30mmol/l30mmol/l尿钠浓度作为阈值以区分低容量血症和等容量血症或高容量血症。几项研究均表明30mmol/l30mmol/l是区分低容与等容和高容的阈值。 如尿钠浓度30 mmol/l 提示动脉血容量过低低渗性低钠血症的治疗如何应用治疗推荐7. Treatment of hypotonic hyponatraemia How to use the treatment recommendations （26）症状严重程度？中重度症状？急性低钠

13、血症循环血量不足？细胞外液量增多？症状严重的低钠血症7.1中重度症状的低钠血症7.2无严重或中重度症状的低钠血症7.3低容量的慢性低钠血症7.4.4高容量慢性低钠血症7.4.2是否是否YNYNYN慢性低钠血症7.4SIAD7.4.3低渗性低钠血症处理流程图7.1.1:严重低钠血症患者（慢或急性）第1小时处理First-hour management, regardless of whether hyponatraemia is acute or chronic 7.1.1.1. We recommend prompt i.v. infusion of 150 ml 3% hypertonic

14、over 20 min (1D). 7.1.1.2. We suggest checking the serum sodium concentration after 20 min while repeating an infusion of 150 ml 3% hypertonic saline for the next 20 min (2D). 7.1.1.3. We suggest repeating therapeuticrecommendations7.1.1.1 and 7.1.1.2 twice or until a target of 5 mmol/l increase in

15、serum sodium concentration is achieved(2D). 7.1.1.4. Manage patients with severely symptomatic hyponatraemia in an environment where close biochemicaland clinical monitoring can be provided (not graded). 7.1.1.1 : 推荐立即静脉输注3%高渗盐水150ml,速度20分钟以上 （1D） 71.1.2: 20分钟后检查血钠浓度并在第二个20分钟重复静脉输注3%高渗盐水150ml （2D） 7

16、.1.1.3： 建议重复以上治疗推荐两次或直到达到血钠浓度增加5mmol/L (2D) 7.1.1.4: 应该在具有密切生化和临床监测的环境下对有严重症状的低钠血症患者进行治疗 7.1.2：1小时后血钠 5 mmol/L,症状改善的接续治疗 7.1.2.1. We recommend stopping the infusion of hypertonic saline (1D). 7.1.2.2. We recommend keeping the i.v. line open by infusing the smallest feasible volume of 0.9% saline unt

17、il cause-specific treatment is started (1D). 7.1.2.3. We recommend starting a diagnosis-specific treatment if available, aiming at least to stabilise sodium concentration (1D). 7.1.2.4. We recommend limiting the increase in serum sodium concentration to a total of 10 mmol/l during the first 24 h and

18、 an additional 8 mmol/l during every 24 h thereafter until the serum sodium concentration reaches 130 mmol/l (1D). 7.1.2.5. We suggest checking the serum sodium concentration after 6 and 12 h and daily afterwards until the serum sodium concentration has stabilised under stable treatment (2D). 7.1.2.

19、1：推荐停止输注高渗盐水（1D） 7.1.2.2：保持静脉通道通畅，输注0.9%盐水直到开始针对病因治疗（1D） 71.2.3：如果可能开始特异性诊断治疗，但至少是血钠浓度稳定（1D） 7.1.2.4：第1个24h限制血钠升高超过10ml，随后每24h血钠升高8mmol. 直到血钠达到130mmol/l 7.1.2.5: 第6h,12h复查血钠，此后每天复查，直到血钠浓度稳定7.1.3：1小时后，血钠 5mmol/l，但症状无改善 7.1.3.1. We recommend continuing an i.v. infusion of 3%hypertonic saline or equiva

20、lent aiming for an additional 1 mmol/l per h increase in serum sodium concentration (1D). 7.1.3.2. We recommend stopping the infusion of 3% hypertonic saline or equivalent when the symptoms improve, the serum sodium concentration increases 10 mmol/l in total or the serum sodium concentration reaches

21、 130 mmol/l, whichever occurs first (1D). 7.1.3.3. We recommend additional diagnostic exploration for other causes of the symptoms than hyponatraemia (1D). 7.1.3.4. We suggest checking the serum sodium concentration every 4 h as long as an i.v. infusion of 3% hypertonic saline or equivalent is conti

22、nued (2D). 7.1.3.1：继续静脉输注3%高渗盐水，使血钠浓度增加1mmol/l. （1D） 7.1.3.2：有下列之一者停止输注高渗盐水： 症状改善， 血钠升高幅度达10mmol/l 血钠达到130mmol/l, （1D） 7.1.3.3: 建议寻找存在症状的低钠血症以外的原因(1D) 7.1.3.4: 只要继续3%高渗盐水输注，建议每隔4小时检测一次血钠（2D）严重低钠血症管理临床建议 最好制备3%盐水备用，以免不时之需或紧急情况下的配置错误 对于体重异常患者，可考虑2ml/kg 的3%盐水输注，不拘泥于150ml. 不必要求重度低钠血症患者症状立即回复，脑功能恢复需待时日，且

23、患者镇静剂应用及插管等均影响判断。此时可参考7.1.2推荐建议处理 记住：如果患者同时有低钾血症，纠正低钾血症则可能使血钠增加严重低钠血症管理临床建议 如根据7.1.2.1建议，达到每小时增加1mmol/l，可应用AdrogueMadias公式计算，但血钠实际的增加可能超过计算值：Na+：钠浓度 (mmol/l); K+, 钾浓度 (mmol/l). 公式1分子是公式2的简化。估测总体水（升）通过体重分数计算：非老年男性是0.6，非老年女性0.5.，老年男性与女性分别是0.5和0.45。通常细胞外液和细胞内液分别占总体水的40%60% （The fraction is 0.6 in non-e

24、lderly men and 0.5 in non-elderly women and 0.5 and 0.45 in elderly men and women respectively. Normally, extracellular and intracellular fluids account for 40 and 60% of total body water respectively.）7.2. 中重度低钠血症（Hyponatraemia with moderately severe symptoms） 7211:立即开始诊断评估 7212:如果可能，停止引起低钠血症的所有治疗

25、7214:立即单次输注3%盐水（或等量）150ml,20分钟以上 7215：每24h血钠升高5mmol/l 7216:第1个24h血钠 10mmol/l 之后每日血钠 10mmol/l，单次静脉输注3%盐水150ml 7316: 4 h后用同样技术检测血钠。 7.4 ：无中重度症状的慢性低钠血症： 7.4.1：一般处理（Chronic hyponatraemia without severe ormoderately severe symptoms） 7411：去除诱因 7412：针对病因治疗 7423：轻度低钠血症，不建议将增加血钠作为唯一治疗 7424：中度或重度低钠血症，第1个24h应避

26、免血钠增加10mmol/l,随后每24h 100 ml/h,提示血钠有快速增加危险。若低容量患者经治疗血容量恢复，血管加压素活性突然被抑制，游离水排出会突然增加，则使血钠浓度意外升高。 如尿量突然增加，建议每2h测血钠。 作为增加溶质摄入的措施，推荐每日摄入0.250.5 /kg尿素,添加甜味物质改善口味。药学家可制备如下袋装尿素口服剂：尿素10g+碳酸氢钠2g+柠檬酸1.5g+蔗糖200mg, 溶于50100ml水中。临床注意事项：Advice for clinical practice7.5:如低钠血症被过快纠正需注意什么？ 7.5.1.1：如果第1个24h血钠增加幅度10mmol/l,第

27、2个24h8mmol/l，建议立即采取措施降低血钠 7.5.1.2：建议停止积极的补钠治疗 7.5.1.3：建议有关专家会诊以讨论是否可以开始在严密尿量及液体平衡监测下以1小时的时间，10ml/kg的速度输注不含电解质液体（如葡萄糖溶液） 7.5.1.4：建议专家会诊，讨论是否可以静注去氨加压素（desmopressin）2ug, 间隔时间不低于8h.指南制定小组临床建议:高容量低钠血症 尚无充分证据支持高容量低钠血症患者增加其血钠可改变患者预后。 对于重度高容量低钠血症患者，指南制定小组认为避免血钠进一步减少是合理的，虽然尚无公开的资料支持此观点。 因此，指南小组 refrained fro

28、m making any statement regarding whether or not to treat this category of patients.指南制定小组临床建议：SIAD 指南制定小组（ the guideline development group ）关于加压素受体拮抗剂问题的意见指南制定小组（ the guideline the guideline development group development group ）关于加压素受体拮抗剂问题的意见 目前常用的加压素受体拮抗剂有： Conivaptan Livivaptan Satavaptan Tolvapt

29、an 关于临床实践中应用加压素受体拮抗剂（vasopressin receptor antagonist）的争论 Rozen-Zvi等综述15篇RCT，共含1619例患者治疗35天后血钠增加平均差（MD）5.27mmol， 1个月后血钠增加MD3.49mmol/l。 两组的死亡风险差别无统计学意义。 两组的不良事件相似。 应用加压素受体拮抗剂快速血钠增加的风险为10%，较安慰剂组高2.5倍。但无渗透性脱髓鞘综合征的报告。American Journal of Kidney Disease. 2010,56,325337 Jaber BL等2011年报告11个RCTDE 1094例患者。血钠浓度

30、第5天轻度增加。MD4.60。两组的病死率无明显差别。American Journal of Medicine. 2011,124,971979 For demeclocycline and lithium, there is some evidence of possible harm, so we advise against their use for management of any degree of chronic hyponatraemia in patients with SIAD. Although vasopressin receptor antagonists do i

31、ncrease serum sodium, the guideline development group judged that based on current evidence, these drugs cannot be recommended. 地美环素和锂可抑制ADH释放。但有证据表明对机体有害。 指南制定小组反对将其用于SIAD患者任何程度的慢性低钠血症 虽然加压素受体拮抗剂确有增加血钠作用，但是指南制定小组认为根据目前资料，不推荐加压素受体拮抗剂临床用于低钠血症。 Indeed, the risk benefit ratio seems to be negative: ther

32、e is no proven outcome benefit aside from increase in serum sodium concentrations, while there are increasing concerns on safety. The most prominent safety related factor is the increased risk for overly rapid correction of hyponatraemia As this risk is greatest in patients with profound hyponatraem

33、ia, the guideline development group wanted to recommend against the use of vasopressin receptor antagonists in this specific patient group. 应用加压素受体拮抗剂的危益比（risk benefit ratio）似乎呈负性：除其增加血钠外，未见其对预后有益。但增加安全担忧。最大的隐患是可能快速升高血钠（而导致渗透性脱髓鞘）。 因在中毒低钠血症患者其危险最大，故指南制定小组不推荐将其用于重症低钠血症患者。 In addition, our concern aro

34、und the toxicity profile of these compounds was increased by reports from the U.S. Food and Drug Administration warning for hepatotoxicity associated with the use of high tolvaptan doses in autosomal dominant polycystic kidney disease. 基于美国FDA公布的tolvaptan 对于多囊肾治疗的肝坏死等不良反应。该类化合物的安全性受到关注！ 根据症状分类： 6131

35、：中度症状 恶心 意识混乱 头痛 6132：重度症状 呕吐 心脏呼吸窘迫 嗜睡 癫痫样发作 昏迷（Glasgow评分8）低钠血症分类的说明 血钠水平：重度低钠血症值为125mmol/l，文献提示110125mmol/l,患者症状明显且严重 进展速度：低钠血症发生于48h更易脑水肿发生，且脑需要48h适应低钠环境，但如果血钠纠正过快，则脑可能再损伤 症状轻重：指南根据急性低钠血症的观察，将症状分为中重度。重度症状者病死率增高。指南避免提及“无症状”低钠血症，因为严格意义上，患者并非无症状，仅仅是表现为不引人注意的注意力不集中 血液渗透压：指南主要涉及低渗性低钠血症，故需首先建立区分高渗与非高渗的

36、临床标准（见6.2）测得的血清渗透压275 mOsm/kg 总提示为低渗性低钠血症,因为有效渗透压绝不会高于总或测得的渗透压。（as effective osmolality can never be higher than total or measured osmolality.） 如果计算的渗透压275 mOsm/kg 则低钠血症可能是低渗，等渗或高渗，这取决于哪些渗透性活性物质的存在和其是否计入公式。（By contrast, if calculated osmolality is275 mOsm/kg, hyponatraemia can be hypotonic, isotonic

37、 or hypertonic, depending on which osmotically active agents are present and whether or not they are incorporated in the formula.） 血容量：低钠血症患者可以分别是低容、等容或高容。传统诊断程序是首先评估患者的容量状态，但所谓容量状态究系指细胞外液量、有效循环血量还是体内液体总量，含义不清。为避免混乱，本指南将其定义为有效循环血量。根据尿渗透压和尿钠浓度进行容量评估 1 以尿渗透压和尿钠对患者容量状态进行评价优于传统容量临床评估方法，故应优先考虑。后者的敏感性与特异性

38、均较低。 受过训练的医生较之未用该方法的高年资医生的诊断水平为优。 Clinical assessment of fluid status We found two studies indicating that in patients with hyponatraemia, clinical assessment of volume status has both low sensitivity (0.50.8) and specificity (0.30.5)。Similarly, it seems that clinicians often misclassify hyponatraem

39、ia when using algorithms that start with a clinical assessment of volume status .Using analgorithm in which urine osmolality and urine sodium concentration are prioritized over assessment of volume status, physicians in training had a better diagnostic performance than senior physicians who did not

40、use the algorithm A urine osmolality 100 mOsm/kg should trigger additional diagnostic testing to determine the underlying cause of hyponatraemia: ultimately classified into hyponatraemia with increased, normal or redu extracellular fluid volume. Because clinical assessment of fluid status is often d

41、ifficult and may lead clinicians down the wrong path, we have consciously steered away from the traditional approach of including it in the algorithm here. Instead, we recommend determining urine sodium concentration on a spot urine sample. It is important to collect the serum and urine sample aroun

42、d the same time to allow correct interpretation of the values. We have selected a urine sodium concentration threshold of 30 mmol/l because several studies indicated good sensitivity and acceptable specificity in distinguishing hypovolaemia from euvolaemia or hypervolaemia (89, 103, 107, 108). This

43、means that a urine sodium concentration 30 mmol/l suggests low effective arterial blood volume, even in patients on diuretics. 尿渗透压100 mOsm/kg 时，应进一步明确低钠血症的原因，最终将其分为高、正常，低细胞外液容量低钠血症。 由于临床常常难于评价液体状况，致使医生做出错误判断。指南推荐检查尿钠含量。应同时采集血液和尿液标本进行检测。 指南选择30mmol/l30mmol/l尿钠浓度作为阈值以区分低容量血症和等容量血症或高容量血症。几项研究均表明30mmol/l30mmol/l是区分低容与等容和高容的阈值。 如尿钠浓度30 mm