2023年6月5日 星期一

SIAD抗利尿激素分泌異常病理解釋與處置原則

重點整理：

  1. 低鈉血症是最常見的電解質異常，影響大約 15% 的住院病人。而大多數是輕度的（≥∼130∼mmol/L），僅4% 的低血鈉 (pNa) 低於 130∼mmol/L
  2. 儘管血清張力低(serum tonicity)，但arginine vasopressin (AVP，即ADH) 過量導致的 inappropriate antidiuresis (SIAD) 是導致非輕度低血鈉的主要原因。
  3. 嚴重的symptomatic低血鈉症狀有嘔吐、癲癇和意識狀態改變，是一種緊急情況，需要緊急IV push 3% 高濃度氯化鈉(100 mL 3% NaCl over 10 min，最多 3 次)以達到 pNa 增加 4-6 mmol/ L、降低顱內壓（ICP）
  4. 為了預防(低血鈉>48小時)在慢性(或未知)onset時間的低血鈉因血鈉上升太快導致滲透性脫髓鞘綜合徵（osmotic demyelination syndrome, ODS），因此 pNa 以24小時內增加 4-8 mmol/L為限，最多 10mmol/L/24 小時（高風險病人如酗酒、營養不良等，應設定較低的增加幅度： 4-6 mmol /L/24 小時）
  5. 每天給<1000 毫升的Fluid restriction (FR) 策略是當前慢性 SIAD 的第一線療法，但僅對大約一半的病人有效。
  6. 有限的證據支持的第二線療法包括tolvaptan, urea, sodium-glucose co-transporter 2 inhibitors (SGLT2i) 或 high-dose salt tablets； 其中，tolvaptan有最高風險導致過度矯正Na血中濃度。
  7. 如果超過鈉校正的上限(校正過快)，則需要使用hypotonic fluid (oral water or intravenous [IV] 5% dextrose)來重新降低 pNa，並考慮並用desmopressin 來減少尿量。


▲Annabelle M Warren and others, Syndrome of Inappropriate Antidiuresis: From Pathophysiology to Management, Endocrine Reviews, 2023 


抗利尿激素（英語：vasopressin，也稱為antidiuretic hormone，簡稱ADH），又稱精胺酸血管加壓素（Arginine Vasopressin, AVP）、血管升壓素、血管加壓素等。


Syndrome of inappropriate diuresis (SIAD)診斷標準：
  1. 血漿滲透壓低: pOsm < 275 mOsmol/kg H2O)
  2. 部正常的尿液滲透壓(過度尿液濃縮): urine osmolality > 100 mOsmol/kg H2O
  3. 體液狀態為euvolemia (absence of signs of hypovolemia or hypervolemia)
  4. Elevated urinary sodium excretion > 30 mmol/L with normal salt and water intake
  5. Absence of other potential causes of euvolemic hypo-osmolality (glucocorticoid insufficiency, severe hypothyroidism)
  6. Normal renal function and absence of diuretic use (particularly thiazide diuretics)

▲Classification of hyponatremia according to tonicity. Syndrome of inappropriate antidiuresis (SIAD) is the most common cause of hypotonic hyponatremia. Adapted from Sahay 2014 with permission, with reference to Spasovski 2014.


▲Useful formulae in the management of hyponatremia. Cr, creatinine; FEUA, fractional excretion of uric acid; mOsm, milliosmoles; Na+ , sodium; UA, uric acid. References (in order): Hiller 1999 (9), Adrogué 1997 (344), Maesaka 1998 (207), and Fürst 2000 (276).


▲急性低血鈉與慢性的發展示意圖，此圖解釋了症狀嚴重程度的典型差異。 
陰影強度是滲透壓的視覺表示。 與腦組織相比，急性低血鈉導致血清/腦脊髓液 (CSF) 的滲透壓相對較低，導致水份以滲透方式(osmotic influx)流入神經膠質細胞(glial cells)以平衡滲透壓梯度，這可能導致腦水腫和癲癇發作、昏迷和死亡。 慢性低血鈉通常更緩慢地發生。 隨著血清/CSF 滲透壓下降，水進入大腦的速度變慢，並與brain osmolytes（包括sodium, potassium, and organic osmolytes （eg: myoinositol, glycerophosphorylcholine, creatine, glutamate, glutamine, taurine））的export 或deactivation互相代償，以平衡滲透壓梯度 。 如果反向過程(生高血鈉)發生得太快，以上機轉產生的低滲透壓大腦(hypotonic brain)容易被快速糾正，這可能會導致osmotic demyelination syndrome。


▲SIAD的原因 (參考 Spasovski 2014)
  • 惡性腫瘤（solid organ (particularly lung and nasopharyngeal), lymphoma）。
  • 肺部疾病（infection, asthma, cystic fibrosis, respiratory failure）。
  • 中樞神經系統疾病（infection, hemorrhage, thrombosis, trauma, tumour, hydrocephalus, autoimmune (multiple sclerosis, Guillain-Barré syndrome）, multiple system atrophy, delirium tremens。 
  • 突發的刺激（nausea, pain, stress, prolonged endurance exercise, general anesthesia, pituitary surgery）。
  • Drugs （見下文Medications that can cause hypotonic hyponatremia）。
  • 特異性(Idiopathic)（“reset osmostat,” cause not yet apparent）。 遺傳性（nephrogenic SIAD）。 
  • AVP，arginine vasopressin。 
    • AVP 儲存在neurosecretory granules中，直到特定刺激（包括 raised serum tonicity and reduced effective circulating arterial blood volume）才會分泌。
▲AVP (精胺酸血管加壓素Arginine Vasopressin)作用於腎 V2 受體的機制。 

ADH在下視丘的室旁核 (Paraventricular nucleus)及視上核 (supraoptic nucleus)合成後被送到腦下垂體後葉貯存，當血中滲透壓(Serum osmolality)升高或體液不足時會刺激腦下垂體分泌ADH。ADH則作用在腎髓質之V2受體(V2 receptor, V2R)，使集尿小管(collecting duct)細胞中cyclic AMP增強，促使水通道蛋白(aquaporin)結合到集尿小管管腔以開啟水通道。此時集尿小管管腔的水便可流入細胞內而達到回收水分的目的。欲知ADH分泌強度最直接的方式是測定血中ADH濃度，但多數實驗室並未常規做此檢驗。由於ADH分泌強度與尿中滲透壓(urine osmolality)或尿比重(specific gravity)皆呈正比，因此可用後兩者數值反映ADH分泌強度。當 ADH分泌越強，尿中滲透壓或尿比重數值就越高。(link)

一般來說，血中滲透壓超過290mOsm/kg左右則ADH開始分泌； 低於270mOsm/kg左右則ADH完全被抑制。ADH對體液流失較不敏感，需失去約10%左右ADH才明顯增加。因此可以說，ADH透過將水分回收或排出體外，把血中滲透壓控制在極窄的範圍 (270~290mOsm/kg)，是穩定血中滲透壓(或血鈉濃度)最重要的激素。

▲Principles of management of acute vs chronic hyponatremia, and potential risks. Intensity of shading is a visual representation of osmolality.


Risk factors for development of osmotic demyelination syndrome following correction of chronic hyponatremia, based on observational data
  • Extremely low serum sodium concentration < 105 mmol/L (or < 113 mmol/)
  • Severe symptoms of hyponatremia: decreased conscious state, vomiting
  • Hypokalemia
  • Alcohol abuse
  • Malnutrition
  • Advanced liver disease
  • Hypotonic urine (indicating water loss/spontaneous correction)

Recommended plasma sodium concentration daily correction targets and limits in current hyponatremia guidelines:

Case reports describe good outcomes after treatment of ODS with glucocorticoids, plasmapheresis, IV immunoglobulin, and zolpidem; however, it is unclear if improvements occurred as the result of these interventions. 
  • Glucocorticoids have been assessed in animal models of ODS and have shown reduced histological damage, but there are conflicting data with respect to mortality benefit. Nevertheless, glucocorticoid therapy after overcorrection is recommended in US expert guidelines for those with baseline a pNa less than 120 mmol/L. Preclinical studies have demonstrated that administration of osmolytes such as urea or myo-inositol can protect against myelinolysis, but they are not routinely recommended for this particular indication. 
  • Plasmapheresis, which may remove “myelotoxins” from the circulation, and/or restore organic osmolytes, is the experimental therapy most frequently reported to have benefit and requires further evaluation. Supportive care measures such as intubation and ventilation, and in patients who survive, prolonged neurorehabilitation may be required. 
  • Optimal management of ODS when it does occur is an important area for future research.


Medications that can cause hypotonic hyponatremia (link)
  • AVP release stimulants or potentiators
    • Antidepressants
      • SSRIs and SNRIs (on initiation)
      • Tricyclics (eg, amitriptyline)
      • MAOI
    • Antiepileptics
      • Carbamazepine, oxcarbazine, sodium valproate, lamotrigine
    • Antipsychotics
      • Phenothiazines (eg, chlorpromazine, thiridazine)
      • Butyropenones (eg, haloperidol)
    • Cancer therapy
      • Vinca alkaloids (eg, vincristine)
      • Alkalating agents (cyclophosphamide, melphalan, ifosfamide)
      • Methotrexate, pentostatin
    • Miscellaneous
      • Tramadol, MDMA (“ecstasy”), interferon, NSAIDs, ACEI (rarely), nicotine, amiodarone, proton pump inhibitors, nicotine, clofibrate, monoclonal antibodies, levamisole, first-generation sulphonylureas (chlorpropramide, tolbutamine), ginkgo biloba 
  • AVP receptor activation
    • AVP analogues: desmopressin, vasopressin, terlipressin (terlipressin a rare cause due to selective V1 receptor activity
    • Receptor crosstalk: oxytocin
  • Reset osmostat
    • Carbamazepine
    • Venlafaxine
  • Natriuretic agents that may mimic SIAD (ie, due to increased urine sodium concentration)
    • Thiazides, indapamide, amiloride, loop diuretics
    • Platinum compounds (eg, cisplatin)
    • Trimethoprim (including co-trimoxazole) 


▲An approach to management of syndrome of inappropriate antidiuresis (SIAD), based on current limited evidence base. pNa, plasma sodium concentration.


SIAD處置建議：
  • Fluid Restriction
  • Tolvaptan
  • Sodium-Glucose Cotransporter 2 Inhibitors
  • Loop Diuretics
  • Demeclocycline
  • Lithium
  • Apelin Analogues

▲Renal physiology in SIAD, and mechanisms of action of tolvaptan, urea, and SGLT2i at the nephron.


延伸閱讀：

  1. Syndrome of Inappropriate Antidiuresis: From Pathophysiology to Management (link)
  2. A Randomized Trial of Empagliflozin to Increase Plasma Sodium Levels in Patients with the Syndrome of Inappropriate Antidiuresis (link)
  3. 抗利尿不當症候群：老問題新觀念(link)
  4. Clinical practice guideline on diagnosis and treatment of hyponatraemia (link)

First release: June.05.2023
於
標籤： ,

沒有留言:

張貼留言

訂閱： 張貼留言 (Atom)