Metabolic alkalosis

0.代償與二分架構(必背⭐)#

• 呼吸代償公式: 預期 PaCO2(mmHg) = 0.7 × [HCO3⁻] + 20 ± 5(另一常用式: PaCO2↑0.6 per HCO3↑1)
  • 實測 PaCO2 高於預期上限 → 合併呼吸酸中毒(常見於 COPD 患者過度代償); 低於下限 → 合併呼吸鹼中毒
• Saline-responsive vs. resistant(用 UCl 判讀, 尿 Cl >20-25 即「resistant/持續刺激」):

• 註: 嚴重低血鉀(<2)時即使 saline-responsive 也可能對鹽水反應差——先補 K

Data from Uptodate:

• Causes of metabolic alkalosis
• The milk-alkali syndrome
• Clinical manifestations and evaluation of metabolic alkalosis
• Pathogenesis of metabolic alkalosis
• Treatment of metabolic alkalosis

1.S/S#

• Related to underlying and associated electrolyte imbalance
• 本身造成的S/S
  • ↑Alb and Ca binding -->↓iCa-->paresthesias, spasm, seizure, coma, arrhythmia...(=hypocalcemia的症狀)
• 註：即使severe metabolic alkalosis, PCO2代償極限為55-60 mmHg(受限於低血氧對周邊化學感受器之通氣刺激；若實測 PaCO2 > 60 mmHg 必合併次發性呼吸性酸中毒，如 COPD 或通氣衰竭)
  • 註：即使severe metabolic acidosis, PCO2不太會代償<10-15mmHg
  • 註：即使severe respiratory alkalosis, HCO3-不太會代償<15mM
  • 註：即使severe respiratory acidosis, HCO3-不太會代償>45mM

2.Bicarbonate physiology#

• 見HypokalemiaHypokalemia-2.Regulation of K
• 註:when alkali loading, alkali 2/3會先分布在ECF, 1/3會 buffered by cells(包含Na-H exchanger, Cl-HCO3- exchanger, alkalosis而↑PFK而↑lactate產生), 之後呼吸代償, 之後腎臟慢慢把alkali排掉(p. tubules維持吸收定量HCO3(所以吸收比例↓, 所以到distal nephron HCO3-變多), ↓distal nephrons排H+(by↓NH3 and other titratable acids excretion), ↑type B intercalated cells排HCO3-); acid loading時身體的代償相反, 不過buffered by cells的比例較高
  • 

3.Etiology#

• Initial events(vs. non-AG metabolic acidosis)
  • Intracellular shifting, non-renal loss/gain, renal, drugs, contraction, post-compensation(functional)
• Maintenance factors
  • GFR↓, (effective arterial volume↓→RAAS↑), other mineralocorticoid excess syndromes↑, increased Na delivery(↓p tubules再吸收NaHCO3(salt diuresis) but↑collecting ducts排H+), hypokalemia)(上述5者使kidney維持metabolic alkalosis), chloride depletion(=dehydration?; Cl↓本身似乎↓distal tubule HCO3 secretion(animal models), 此外也導致type B intercalated cell的Pendrin無法做Cl-HCO3 exchange)
  • 也就是說Maintenance factors就是在問Why is the excess HCO3 not being excreted in the urine?
    • 由(前->後; GFR->proximal tubules製造NH3↑(hypokalemia)->RAAS↑->hypochloremia)
  • Hypokalemia使intracellular acidosis而↑p. tubules NHE3, ↑p. tubules製造NH3, 也↑type A intercalated cell的apical H+-K+ ATPase; 也因為↑Ang II而↑p. tubules NHE3/Na/water resorption; 以上綜合維持metabolic alkalosis
    • 
• UCl<20mM
  • NG decompression, vomiting
    • 導致Liver, pancreas, GI secrete出來的HCO3-不和H+ react而直接被再吸收(=loss H+)
    • 某些Antacid(MgO, Al(OH)3, CaCO3)不會metabolic alkalosis(因為雖然會局部↓H+, 但Mg, Al, Ca等陽離子會再和HCO3- bind而loss in stools)
      • 但若同時給Resonium因為會使Na-cation exchange, 導致HCO3-被和Na再吸收-->metabolic alkalosis
  • Chloride diarrhea(congenital(AR, loss of function mutation of ileal/colon Cl-HCO3 exchanger; SLC26A3; 可用PPI治療) or villous adenomas(可能主要來自於hypokalemia and volume depletion, 因為stool仍呈鹼性...) or laxative abuse(小心這些人也可能偷用diuretics and 催吐(為了減肥or厭食症)))
    • Also hypokalemia
    • 注意：一般的diarrhea是non-AG metabolic acidosis, 而因為stool中的chloride少, 所以排出很多NH4Cl(==>high UCl); laxative abuse可以表現成一般的diarrhea or chloride diarrhea
  • Cystic fibrosis(sweat loss NaCl, K+)
    • 不是說也會ROMK dysfunction而類似Bartter's syndrome type II?
  • Sweating(可normal pH or metabolic alkalosis)
  • Previous loop/thiazide diuretic use(利尿劑使用中為高 UCl >20-25，但停藥數天後因續發性容積收縮活化 RAAS，UCl 轉為 <10-20 mEq/L，轉為 Saline-responsive，補鹽水可校正)
  • Posthypercapnic alkalosis
    • 小心OsA者可能半夜hypercapnia而代償性HCO3-↑, 到了早上抽gas時已無hypercapnia但殘存posthypercapnic alkalosis!!
  • Dehydration(雖然secondary RAAS↑ 不過UCl↓, 是因為p. tubules再吸收NaCl也↑?)(renin-secreting tumor 因續發性高醛固酮＋高血壓＋容積擴張, 持續排鉀排氫, UCl 為高(>20-25 mEq/L), 屬 saline-resistant)
    • Due to ↓GFR and secondary RAAS↑(↑HCO3 resorption by p. tubules(因為Ang II↑apical NHE3 and H+ATPase and ↑basolateral NBC1) and ↑H+ secretion by collecting ducts)
      • 機轉可見-hypokalemiahypokalemia-2.Regulation of K
  • Contraction alkalosis
    • Any etiology cause loss high NaCl and low HCO3- concentration fluid, and dehydration...
  • Milk-alkali syndrome(急性嘔吐與脫水期 UCl <20；若合併明顯高血鈣利尿與重碳酸尿, UCl 可波動上升)
    • Mechanism
      • Intake of Ca(->hypercalcemia->本身促進renal H+ secretion(why?為了避免Ca-P沉積?); 註:但hypercalcemia本身也可以type I RTA(due to Ca-P depositions??)...) + antacid(Soda) +/- vomiting ==> metabolic alkalosis(本身促Ca, Mg, P reuptake by distal tubules, 見hypercalcemiahypercalcemia-Physiology of Ca regulation; 此外metabolic alkalosis也會激活CaSR-->diuresis-->dehydration; 註:感覺很奇怪, 有促進CaSR排鈣但又促進distal tubules吸收鈣...) + NDI(hypercalcemia) + dehydration(->RAAS↑ and ↑proximal tubules reuptake NaHCO3) + AKI(->↓GFR->retention of HCO3)
        • 只↑Intake of Ca不太會hypercalcemia, 因為身體會↓calcitriol, 除非Ca intake>10-15g/d
          • 但有些人的Calcitriol不太會被suppressed, 原因未知(但吃Ca片可造成mild hypophosphatemia(若Ca來源是milk則不會, 因為milk很多P)-->increased calcitriol-->可能是造成milk alkali syndrome的原因之一)
        • 小心一些Ca來源：betel nuts, nicotine-substitute chewing gum
    • Risk factors：elderly, pregnancy(elevated calcitriol level), eGFR↓(含用ACEI/ARB/NSAID...), dehydration
    • 可acute~chronic
    • Tx
      • DC Ca, DC vitamin D, DC antacids
      • NaCl hydration +/- Lasix
        • 通常回復蠻快的, even transient hypocalcemia(due to longterm suppression of PTH而暫時代償不好)
  • After Tx of L-lactic acidosis/ketoacidosis
    • 因為lactate/ketone代謝回HCO3- + 外加Rolikan + 腎臟之前努力排酸 +/- volume contraction/hypokalemia
  • Massive nonreabsorbable anions(penicillin...)(典型 UCl <20;因 Na 多與該陰離子共同排出而非與 Cl 共排, 且管腔負電位↑促進排鉀排氫)
    • 因為distal nephron lumen中負電↑, 所以排K+, 排H+↑
  • Alkali loading(含HCO3, citrate(RCA, TPE, transfusion...), lactate, acetate...) without volume overload
    • 單純的Alkali loading若沒有maintenance factors不太會metabolic alkalosis
  • Non-severe hypokalemia
    • Vs.下述severe hypokalemia
• UCl>20(25)mM (常>40mM)
  • Bartter/Gitelman's syndrome[(UCl 多>40mM), 因為equal to intake]
  • Loop/thiazide diuretics use
    • 抑制NKCC2, NCC, 導致distal site↑Na resorption(=↑ENaC?), 搭配bicarbonaturia, Cl- distal delivery↑, secondary RAAS↑, 導致distal H+ and K+ secretion↑
    • Also [volume depletion(->secondary RAAS+contraction alkalosis) and hypokalemia]-->increase proximal tubules NaHCO3 resorption
    • UCl會高高(用diuretics時)低低(藥效過時)(vs. Bartter's syndrome, Gitelman's syndrome會persistent UCl高)
  • Hyperaldosteronism/mineralocorticoid excess-like status(見hypokalemia(also RAAS表)-RAAS↑ (UCl high) [RAAS系列, diuretics系列, vomiting]) (including steroid use)
    • Renin↓+Ang II↓=>proximal tubules NaHCO3 resorption↓(though hypokalemia本身-->↑proximal tubules NaHCO3 resorption↑(因為intracellular acidosis?)), overall NaHCO3, NaCl resorption↓=>Na delivery to distal tubules↑
    • Na delivery to distal tubules↑ + hyperaldosteronism ==>metabolic alkalosis + hypokalemia
    • Though Cl delivery to distal tubules↑-->↑type B intercalated cells Cl-HCO3 exchange 但也↑電位差使K+, H+ secreted by collecting ducts↑(因為Cl...等anions吸收比Na慢)
  • Alkali loading(含HCO3, citrate(RCA, TPE, transfusion...), lactate, acetate...) with volume overload
    • UCl>20的原因還是volume overload導致proximal tubules↓吸收NaCl, NaHCO3(→ 見上文 Alkali loading without volume overload)
      • 所以若沒有volume overload UCl可<20
  • Severe hypokalemia(K<2)(UCl↑ due to impaired distal tubular Cl reabsorption(機制未知)->導致電位差更大-->loss K+, H+↑)
    • 註:Non-severe hypokalemia可UCl<20
    • (見HypokalemiaHypokalemia-1.S/S-Renal abnormalities)
    • 小心from hypomagnesemia(除了會↑hypokalemia之外, 本身也會↑renin)
  • Hypomagnesemia
    • 除了因為會hypokalemia之外, 本身也會↑renin
  • Pendred syndrome
    • AR; SLC26A4 (solute carrier family 26, member 4 gene), located on chromosome 7 (7q31) mutation
      • 註:SLC26AX好像都和Cl- transport or exchanger有關
    • 下圖的Type B intercalated cell的apical HCO3-Cl- exchanger(=Pendrin) loss of function mutation, 平常沒有electrolyte nor metabolic alkalosis(因為NCC...會代償), 但若使用thiazide, 會導致severe metabolic alkalosis and hypovolemia
    • 此外因為Pendrin也和thyroid glands uptake iodide and inner ear electrolyte balance有關, 所以也會primary hypothyroidism with goiter and sensorineural deafness
      • 

4.Approaching#

• 大多by history即可知原因
• 若沒有明顯原因
  • Check UCl(見上述), UpH(意義?, 主要是配合UNa看, 因為if UpH>7表bicarbonaturia超過proximal tubules吸收上限, 此時雖然就算脫水RAAS↑, UNa仍不會<25), UNa(UNa其實不太有意義, 因為雖然volume depletion-->RAAS↑-->↓UNa, 但(Na or K)HCO3 lost in urine(UpH>7)-->可使UNa↑如前述), Alb, SCa, K
    • If high UCl-->Also check ACTH/Cortisol, renin/aldosterone
  • 

5.Tx#

• Tx of underlying causes(hypokalemia, GI, drugs, bicarbonate origin, hyperaldosteronism, dehydration...)
  • 若refractory vomiting or persistent NG decompression/drainage
    • Consider H2 blocker or PPI
  • If fluid overload with effective arterial volume不足者; 如:CHF, LC...
    • 不可NaCl hydration; Tx hypokalemia by KCl
    • Consider Amiloride, Aldactone(先) +/- Azol(後)(250-500mg QD-BID, 注意Azol ↑K+ loss due to ↑distal delivery of NaHCO3, 要補回來)
  • In ACKD/AKI/reduced GFR
    • Consider low HCO3 RRT
  • If (severe metabolic alkalosis(like pH>7.55 or HCO3 >50mM) or failed to conventional Tx) and (無法RRT)
    • Consider NH4Cl(=NH3+HCl; NH3會metabolized to Urea(所以其實liver不好或GFR↓不太能用))
    • Consider ArginineHCl(but 1.not FDA-approved 2.may cause hyperkalemia(因為Cationic arginine進入cells會把K交換出來))
• NaCl/KCl hydration if UCl<20 except (fluid overload with effective arterial volume不足者; 如:CHF, LC..., 不過這些人若hypokalemia仍要矯正)
  • 會先NaHCO3/KHCO3 lost in urine(因為no dehydration and ↓RAAS-->↓proximal resorption of HCO3 and ↓distal H+ secretion) and Cl is retained(因為Cl-在p. tubules的paracellular resorption permeability比HCO3-好, 所以給NaCl時, 會先吸收Cl而非HCO3-?), then after chloride and volume repletion-->↓proximal Cl resorption使Cl-到type B intercalated cells做Cl-HCO3 exchange繼續排HCO3)
  • 給予Na/K with non-resorbable anions會無法矯正metabolic alkalosis, 因為non-resorbable anions會和NH4+ or H2PO4 or Na+ or K+一起排出去(1.會維持collecting ducts電位差-->loss K+, H+↑; 2.無法做Cl-HCO3 exchange)-->導致維持metabolic alkalosis and hypokalemia
    • 有study研究Cl- repletion甚至比K+ repletion更重要, 不過當然仍要K+ repletion