低鈉血癥如何診治

1、低鈉血癥如何診治,,水、鈉代謝的調(diào)節(jié),定 義,血清鈉＜135mmol/L為低鈉血癥； 僅反映鈉在血漿中濃度的降低，并不一定表示體內(nèi)總鈉量的丟失，總體鈉可以正常甚或稍有增加。臨床上極為常見，特別在老年人中。主要癥狀為軟弱乏力、惡心嘔吐、頭痛思睡、肌肉痛性痙攣、神經(jīng)精神癥狀和可逆性共濟(jì)失調(diào)等。,分類,根據(jù)滲透壓低滲性低鈉血癥等滲型低鈉血癥高滲性低鈉血癥根據(jù)低鈉血癥發(fā)生時(shí)的血容量變化低血容量性低鈉血癥 失鈉多于失

2、水。 血容量正常性低鈉血癥 總體水增加而總鈉不變。 高血容量的低鈉血癥 總體水增高大于血鈉升高,根據(jù)血鈉降低的程度可分為 重度低鈉血癥＜120mmol/L中度低鈉血癥＜130mmol/L輕度低鈉血癥＜135mmol/L 此外還有假性低鈉血癥，見于明顯的高脂血癥和高蛋白血癥。,病 因,假性低鈉血癥（滲透壓正常）高脂血癥、高蛋白血癥（顯著升高）高滲透性性低鈉血癥（高血糖、甘露醇或甘油治療）低血容量性低

3、鈉血癥胃腸道消化液丟失（如嘔吐、腹瀉、胰腺炎及胰腺造瘺和膽瘺等； 皮膚水鹽丟失（大量出汗、大面積三度燒傷、胰腺纖維性囊腫）體腔轉(zhuǎn)移丟失 （小腸梗阻、腹膜炎、急性靜脈阻塞、嚴(yán)重?zé)齻龋┠I性失鈉（慢性腎臟疾病、失鹽性腎病、鹽皮質(zhì)功能減退、SIADH、糖尿病酮癥酸中毒、利尿劑）腦性鹽耗損綜合征（下視丘腦或腦干損傷引起）,,血容量正常性低鈉血癥SIADH糖皮質(zhì)激素缺乏腎病綜合癥不適當(dāng)利尿精神性多飲甲狀腺功能減退癥嚴(yán)重慢性肺

4、部疾病、惡液質(zhì)、營(yíng)養(yǎng)不良高血容量性低鈉血癥充血性心力衰竭肝功能衰竭慢性腎功能衰竭腎病綜合征,SIADH,惡性腫瘤（肺燕麥細(xì)胞癌、前列腺癌、胸腺癌、淋巴瘤等）肺部縱膈疾病- 肺炎、曲霉病、膿腫、TB, PPV中樞神經(jīng)系統(tǒng)疾病 – 膿腫、創(chuàng)傷、腦膜炎、中風(fēng)、SAH內(nèi)分泌疾病– Addison病、甲減手術(shù)后急性間歇性卟啉癥 藥物性SSRI、苯丙胺相關(guān)藥、長(zhǎng)春新堿、環(huán)磷酰胺，卡馬西平，溴隱亭NSAIDS：通過降低腎臟的

5、前列腺素,低血容量性低鈉血癥（一）,,低血容量性低鈉血癥（二）,,正常容量或高容量性低鈉血癥（一）,,正常容量或高容量性低鈉血癥（二）,,病理生理,低鈉血癥從病因來說，不外是鈉的丟失和耗損，或者是總體水相對(duì)增多，總的效應(yīng)是血漿滲透壓降低(血鈉濃度是血漿滲透壓維系的主要成分)。失鈉又常伴有失水，不管低鈉血癥的病因?yàn)楹?，有效血容量均縮減，從而引起非滲透壓性ADH釋放，以圖增加腎小管對(duì)水的重吸收，以免血容量進(jìn)一步縮減。然而這種保護(hù)機(jī)制更加重

6、了血鈉和血漿滲透壓的降低，這種代償機(jī)制發(fā)生于有效血容量縮減的早期，當(dāng)血[Na+]下降到＜135mmol/L時(shí)，ADH釋放則被抑制。,正常時(shí)細(xì)胞內(nèi)滲透壓保持穩(wěn)態(tài)平衡。當(dāng)血漿鈉濃度降低，細(xì)胞外液滲透壓下降，細(xì)胞外水流血細(xì)胞內(nèi)，使細(xì)胞腫脹，以致細(xì)胞功能受損甚至破壞，其中以腦細(xì)胞腫脹，可導(dǎo)致低鈉血癥最嚴(yán)重的臨床表現(xiàn)。血容量縮減如果得不到糾正，則可使血壓下降，腎血流量減少，腎小球?yàn)V過率降低，可導(dǎo)致腎前性氮質(zhì)血癥。,臨床表現(xiàn),低鈉血癥的臨床表現(xiàn)嚴(yán)

7、重程度取決于血鈉水平和血鈉下降的速率。血鈉在125mmol/L以上時(shí)，極少引起癥狀；鈉在125～130mmol/L之間時(shí)，也只有胃腸道癥狀。此時(shí)主要癥狀為軟弱乏力、惡心嘔吐、頭痛思睡、肌肉痛性痙攣、神經(jīng)精神癥狀和可逆性共濟(jì)失調(diào)等。,,腦水腫臨床表現(xiàn)有抽搐、木僵、昏迷和顱內(nèi)壓升高癥狀，嚴(yán)重可出現(xiàn)腦幕疝。如果低鈉血癥在48h內(nèi)發(fā)生，則有很大危險(xiǎn)，可導(dǎo)致永久性神經(jīng)系統(tǒng)受損的后果。慢性低鈉血癥者，則有發(fā)生滲透性脫髓鞘的危險(xiǎn)，特別在糾正低鈉血

8、癥過分或過快時(shí)易于發(fā)生。除腦細(xì)胞水腫和顱高壓臨床表現(xiàn)外，由于血容量縮減，可出現(xiàn)血壓低、脈細(xì)速和循環(huán)衰竭，同時(shí)有失水的體征?？傮w鈉正常的低鈉血癥則無(wú)腦水腫臨床表現(xiàn)。,實(shí)驗(yàn)室檢查,血生化及電解質(zhì)測(cè)定血漿滲透壓測(cè)定 尿滲透壓測(cè)定 血BNP測(cè)定點(diǎn)尿鈉濃度測(cè)定 血尿酸水平,滲透壓,血漿滲透壓（Posm)Posm = 2 (Na+K) +血糖+血尿素氮正常 = 2 (140) + 5 + 5 = 290 (275-290 m

9、M) 尿滲透壓（UOSM） :正常: 400-500 mM最大稀釋 50-100 mM (USG 1.002-1.003)最大濃縮 900-1200 mM (USG 1.030-1.040)濃縮尿: > 500 mM (至少!), USG > 1.017UOSM > POSM is not enough to R/O Diabetes Insipidus,,,診 斷,確定是否為真正的低鈉血癥血漿滲

10、透壓（Posm ）正常范圍 280-295mOsm/kg如果 >295 mOsm/kg高血糖或甘露醇的使用（高滲性低鈉血癥）如果在280-295 mOsm/kg之間 :假性低鈉血癥：高脂血癥或高蛋白血癥如果<280 mOsm/kg評(píng)價(jià)容量狀態(tài),,血漿滲透壓 < 280 mOsm/kg高容量性:充血性心力衰竭、肝硬化、腎病綜合癥、急慢性腎功能衰竭正常容量性： SIADH、甲減、精神性多飲、腎病綜合癥不

11、適當(dāng)利尿、嗜啤酒狂、手術(shù)后、鈉攝入不足、極低蛋白飲食等低容量性胃腸消化液丟失、皮膚出汗、利尿劑使用、腦鹽耗綜合癥、體腔轉(zhuǎn)移丟失、鹽皮質(zhì)激素不足（Addison?。?,低鈉血癥的診斷思路,低鈉血癥的治療應(yīng)根據(jù)病因、低鈉血癥的類型、低鈉血癥發(fā)生的急慢及伴隨疾病而采取不同處理方法，故強(qiáng)調(diào)低鈉血癥的治療應(yīng)個(gè)別化，但總的治療措施包括： 　　①去除病因； 　?、诩m正低鈉血癥； 　?、蹖?duì)癥處理； 　?、苤委熀喜Y。,治 療,低鈉血癥的糾

12、正速度,24小時(shí)內(nèi)升高<10-12mmol/L，48小時(shí)內(nèi)血鈉升高<18 mmol/L,治 療,急性低鈉血癥 =腦水腫、腦疝方法:去除病因癥狀輕到中度:無(wú)需進(jìn)一步干預(yù)治療；嚴(yán)重癥狀:高滲鹽水輸注(3%) 3% NaCl檢測(cè)輸液速度-避免中樞腦橋脫髓鞘病變檢測(cè)血鈉水平 q2h24小時(shí)內(nèi)升高<10-12mmol/L，48小時(shí)內(nèi)血鈉升高<18 mmol/L,Verbalis, Joseph G.

13、, 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

14、 療,慢性低鈉血癥 = 腦適應(yīng)重要是控制低鈉血癥的糾正速度 ?腦適應(yīng)性、細(xì)胞內(nèi)溶質(zhì)外溢血鈉糾正過快，大腦容易受損傷…由于腦細(xì)胞不能重新攝取溶質(zhì)，細(xì)胞萎縮“中樞腦橋髓鞘溶解” / “滲透性脫髓鞘作用” 大腦局限在顱內(nèi)，構(gòu)音困難、吞咽困難、癲癇、神智改變、四肢輕癱、低血壓1-3天內(nèi)糾正低鈉血癥24小時(shí)內(nèi)升高<10-12mmol/L，48小時(shí)內(nèi)血鈉升高<18 mmol/L,Hyponatremia Treatmen

15、t Guidelines 2007: Expert Panel Recommendations." The American Journal of Medicine 120 (2007): S1-S21.,治 療,慢性低鈉血癥 （續(xù)）低血容量性: 生理鹽水- 恢復(fù)組織灌注正常容量性和高容量性限制液體攝入 袢利尿劑/ 鹽片口服 血管加壓素受體拮抗劑--考尼伐坦、托伐普坦其他地美環(huán)素引起腎性尿崩癥2-5天發(fā)生

16、嚴(yán)重的多尿? 高鈉血癥腎毒性、光敏感、皮疹尿素長(zhǎng)期治療有效 (5年)動(dòng)物模型顯示有益鋰劑下調(diào)血管加壓素刺激的水通道蛋白2的表達(dá)有效性不確定引起腎性尿崩癥,hyponatremia Treatment Guidelines 2007: Expert Panel Recommendations." The American Journal of Medicine 120 (2007): S1-S21.,慢性低鈉血

17、癥（等容量或高容量性）,無(wú)癥狀:首選病因治療限制水的攝入袢利尿劑/鹽片攝入抑制ADH釋放：地美環(huán)素V2 受體拮抗劑考尼伐坦、托伐普坦有癥狀:（低鈉性腦病、嚴(yán)重腦水腫）3% 高滲鹽水Desired change in Na × TBWTBW: 0.6 × weight (kg) in men & 0.5 × weight (kg) in women緩慢糾正，避免并發(fā)癥,抗利尿激素

18、受體（AVPR）拮抗劑,一種新的治療低鈉血癥的藥物，阻斷V2R與抗利尿激素受體結(jié)合，進(jìn)而抑制腺苷酸環(huán)化酶信號(hào)途徑從而排除自由水但是對(duì)尿鈉、尿鉀無(wú)作用。Conviptan已被美國(guó)FDA批準(zhǔn)用于等容量和高容量性低鈉血癥患者的應(yīng)用，而在2009年，歐洲EMEA和美國(guó)FDA均批準(zhǔn)Tolvaptan用于SIADH患者低鈉血癥的治療。另外目前用于臨床試驗(yàn)研究階段的藥物還包括Lixivaptan和Satavaptan。,Multi-center,

19、 double-blind, placebo controlled, randomly assigned (4days)Conivaptan 30min LD (20mg diluted to 100ml D5W) infusion ? 96hr CIV days 1-4 (diluted to 250ml)40mg/day80 mg/day Placebo 100ml D5W as LD ? 250 ml D5WImport

20、ant Exclusion Criteria:Hypovolemic hyponatremiaCardiac problems: Hyponatremia requiring immediate treatmentMedications interacting with CYP4503A4Other medications,Assessment of the Efficacy and Safety of Intravenous

21、 Conivaptan in Euvolemic and Hypervolemic Hyponatremia,American Journal of Nephrology 27 (2007): 447-57,Time to increase >/= 4mEq/L :Conivaptan 40mg/day: 24 hoursConivaptan 80mg/day: 10 hoursPBO: no increase within

22、 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

23、 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 (

24、n=17),Assessment of the Efficacy and Safety of Intravenous Conivaptan in Euvolemic and Hypervolemic Hyponatremia,Discontinuation was mainly due to Infusion site reactionsOther ADRs: hypotension, postural hypotension, py

25、rexia, hyperkalemia, infusion site thrombosis,,Prospective, multi-center, randomized centrally, double-blind, placebo controlledConducted 2 trials to assess reproducibility (SALT-1 & SALT-2)Tolvaptan 15mg tab 1 tab

26、 PO Daily x 30 days OR PBOImportant Patient Population Criteria:InclusionEtiologies: CHF, cirrhosis or SIADHExclusion Criteria:Other etiologiesHypovolemic hyponatremiaOther cardiac diseases (post-MI, SVT, SBP<9

27、0)Serum Na <120 mmol/L w/ neurological impairmentPoor prognosis not tolerating fluid shifts: short-term survival,Tolvaptan, a Selective Oral Vasopressin V2-Receptor Antagonist, for Hyponatremia,New England Journal o

28、f Medicine 355 (2006): 2099-112,,Similar Baseline Characteristics across study groups (except height in SALT-2), Mean baseline Na: ~128 mEq/LCo-Administration/Co-intervention: Fluid restriction was not mandatory; treatm

29、ent 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 37,,Valu

30、es were statistically significantIncreases in Na were greater in Tolvaptan group than PBO in both trials and in both stratifications at Day 4 and much more at Day 30Increases were more rapid (by day 4) and greater (mar

31、ked 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

32、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

33、 “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 arm

34、,Tolvaptan (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%

35、)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 d

36、ue 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, vomitingComplet

37、ed 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-Recep

38、tor 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 An