Metabolic Disorders of Acid Base Balance

Metabolic Disorders of Acid Base Balance
경희대학교 의과대학 내과학교실 문 주 영

Contents 1. 산염기 대사의 기본 생리와 장애 2. 대사성 산증의 진단과 치료

pH 0.1N HCl (ml) 7.44 7.14 Dog (19.7 Kg) Buffer 1.84 Water (11.4 L)
7.0 6.0 5.0 4.0 3.0 2.0 1.0 Buffer Dog (19.7 Kg) pH 1.84 Water (11.4 L) 0.1N HCl (ml)

1. 혈중 pH : [H+] Homeostasis
Range of [H+] in ECF : 16 ~ 160 nmol/L (pH 7.8 ~ 6.8) Normal arterial [H+] : 40 nmol/L (pH 7.4) Strongly involved in enzymatic process - essential to cellular function especially excitable cells (cardiac cells, neuromuscular system) 보통 전해질 농도는 mEq/L인데 비해, [H+]의 농도는 nEq/L로, [H+]의 농도가 다른 전해질 농도에 비해 백만분의 일이라는 의미이다 따라서, pH라는 log 식으로 표시한다

동맥혈의 pH와 [H+]의 관계 pH [H+] (nEq/L) 7.7 20 7.6 26 7.5 32 7.4 40 7.3 50
7.2 63 7.1 80 7.0 100

Lung and Kidney in CO2 Buffer System
H+ + HCO3- H2CO3 H2O CO2 Lung and Kidney in CO2 Buffer System At equilibrium [H+] = 24 X PCO2 [HCO3-] Changes in volume of ventilation Changes in renal H+ excretion & HCO3- reclamation Independently regulated 40 = 24 X 24 = 40

산염기 대사의 생체내 조절 생체 완충계 2. 호흡성 조절 3. 신장의 산염기 조절 기능

Relative effective of response to acid load (%)
Renal regulation 100 80 60 40 20 Respiratory compensation ICF buffer Relative effective of response to acid load (%) ECF buffer hours days Time Sequence of Buffering

Production ( 1 mmol/kg/day)
Endogenous Acid Production ( 1 mmol/kg/day) ECF (Blood) HCO3- (40 – 50%) Protein- Hb- Phosphate2- ICF Protein- Phosphate2- HCO3- BUF- + H+ HBUF Renal Acid Excretion Bone CaCO3 Sources of Buffers for Reaction with H+ Ions Added to The Body Fluids

Acid Production = Acid Gain = Anion Gain
H+ A Na + HCO3- NaA CO2 + H2O

Na+ Alkali (HCO3- ) Loss Loss of HCO3- = normal anion = hyperchloremia
Cl - A- Na+ Cl - Cl - Cl - = = = HCO3- HCO3- A- HCO3- A- A- Normal Acid Gain Alkali Loss

Na - (Cl + HCO3) = UA – UC = Anion Gap
Serum Anion Gap 전기 화학적 평형에 도달하기 위해 음전자와 양전자가 동일 농도로 평형을 이루어야 한다. Na + UC = Cl + HCO3 + UA Na - (Cl + HCO3) = UA – UC = Anion Gap UA – UC는 비교적 풍부한 측정되지 않은 음전자의 합으로, anion gap(AG)이라고 부른다. Normal : mmol/L (ISE : 3 – 11 mmol/L) 일반적으로 측정하는 Na, Chloride(Cl), HCO3 외에도 측정되지 않은 양전자(unmeasured cations, UC)와 음전자(unmeasured anions, UA)들 모두 평형을 이루는데 참여한다.

Determinants of the anion gap
Na+ + UC = Cl- + HCO3- + UA Na + - (Cl - + HCO3 -) = UA – UC = Anion Gap Unmeasured anions Unmeasured cations Albumin (15mEq/L) Calcium (5 mEq/L) Organic acids (5 mEq/L) Potassium (4.5 mEq/L) Phosphate (2 mEq/L) Magnesium (1.5 mEq/L) Sulfate (1 mEq/L) Total UA : (23 mEq/L) Total UC : (11 mEq/L) Anion gap = UA – UC = 12 mEq/L *if albumin is reduced by 50%, anion gap = 4mEq/L 이같은 hypoalbuminemia의 영향을 피하기 위해서는 AG을 알부민 (g/dL)과 phosphate(PO4) (mg/dL) 농도를 이용하여 계산하는 방법이 있다 AG = [2 x albumin] + [0.5 x PO4]

CO2 Buffer System H2O [CO2]dis H2CO3 H+ HCO3-
Ka = Ka’ = [CO2]dis [H2O] [CO2]dis [CO2]dis PCO2 Ka’ X [CO2]dis [H+] = = 800 x = 24 x [HCO3-] [HCO3-] [HCO3-] *[CO2]dis = 0.03 x PCO2 Total CO2 = [CO2]dis + [H2CO3] + [HCO3-] = 0.03 x PCO2 + [HCO3-] (normal PCO mmHg) = [HCO3-]

Function of Lung in Acid Base Regulation
Normal : pH 7.40 : [H+] 40 nmol/L, HCO mmol/L PCO2 40 mmHg : [CO2]dis 1.2 mmol/L add 2 mmol [H+] H+ + HCO H2CO H2O + CO2 = = Lung Normal lung No lung [CO2]dis 1.2 34.6 nmol/L (pH 7.36) [H+] = 800 x = 800 x = [HCO3-] 22 3.2 116 nmol/L (pH 6.93) [H+] = 800 x = 22

Respiratory Compensation to Metabolic Acid Base Disorders
Never normal pH (7.40) by respiratory compensation Respiratory depth (volume), not rate 1. Metabolic acidosis Δ HCO mmol/L Δ PCO2 1 mmHg - limit : PCO mmHg 2. Metabolic alkalosis Δ HCO mmol/L Δ PCO2 1 mmHg - limit : PCO mmHg (hypoxic drive)

with equimolar HCO3- reabsorption
Urine Acidification Urine Net Acid Excretion =[NH4+] + [Titratable Acidity] – [HCO3-] HCO3- reabsorption : proximal tubule, Henle loop (TAL) H+ excretion (normal : 1 mmol/Kg/day) 1) Titratable acidity : NHE (phosphate>> sulfate, urate) 2) Ammoniagenesis (NH4Cl) : H+ or H +- K + ATPase at CD with equimolar HCO3- reabsorption

Proximal Tubular Acidification
CA II NHE ATP 2K+ 3Na+ Na+ H+ NBC HCO3- H2CO3 CO H2O H2O + CO2 Proximal Tubule Lumen AQP1 CA IV Na+/H+ exchanger (NHE) H+-ATPase Na+/K+-ATPase Na+/HCO3- cotransporter (NBC) Cl-/HCO3- exchanger (AE) (S3 ) Proximal Tubular Acidification AE Cl-

Proximal tubules Interstitial Na+ ATP Luminal H+ H+
HCO3- Luminal H+ + HCO H2O + CO2

Proximal tubules 1Na+, 3HCO3- 3Na+ Interstitial ATP 2K+ H+ + HCO3-
H2O + CO2 H+ Na+ ATP H+ Luminal HCO3- HCO3- HCO3- HCO3-

Proximal tubular acidosis (Type II RTA)
HCO3- 흡수 장애 Alkali loading test (NaHCO3 infusion) UHCO3 x PCr Fe HCO3- = ——————————— x 100 PHCO3 x Ucr Type 2 : marked bicarbonaturia FeHCO3 > 15-20% high urine pH (>7.5)

Acidification at Collecting Duct
Lumen H+-ATPase H+/K+-ATPase Cl-/HCO3- exchanger (AE) A H2O + CO2 CA II ATP H+ H+ + HCO3- AE1 H+ ATP Cl- K+ Aldosterone Intercalated A Cell of CD H+-ATPase AE Acidification at Collecting Duct

Urine Acidification by Hydrogen Excretion
Lumen Blood 3Na+ PT HPO42- Na+ ATP NHE 2K+ H+ HCO3- NBC H2CO3 CA Na+ NaH2PO4 (Titratable acid) H2O + CO2 CD NH3 H+ ATP H+ HCO3- AE1 H2CO3 Cl- CA NH4Cl (Ammonium) H2O + CO2 Aldosterone Urine Acidification by Hydrogen Excretion and Equimolar Alkali (HCO3-) Reclamation

Distal tubular acidosis (Type I RTA)
H+ 배설 장애 Cause : idiopathic, autoimmune disease, ureter obstruction, volume depletion, amphotericin B toxicity Alkali loading test (NaHCO3 infusion) Type 1 : Fractional excretion of bicarbonate will be less than 3 percent and the urine pH will remain relatively stable Urine-Blood PCO2 ≤30 mm Hg during NaHCO3 loading ICC H+ ATP HCO3- H+ H2CO3 H2O + CO2

Urine NH4+ (mmol/L) U-B PCO2 (mmHg)
Urine NH4+ after Acid Loading vs U-B PCO2 after Alkali Loading (Kim et al. Kidney Int, 2004; 66(2):761) 100 75 50 25 Urine NH4+ (mmol/L)  dRTA  control U-B PCO2 (mmHg)

Normal arterial blood pH : 7.40 + 0.05
Definition Normal arterial blood pH : 1. Acidemia : pH < 7.35 Alkalemia : pH > 7.45 ‘ –emia’ : dependent of blood pH 2. Acidosis : process of acid gain or alkali loss Alkalosis : process of alkali gain or acid loss ‘ –osis’ : not dependent of blood pH

ABGA : pH 7.40, PCO2 60 mmHg, HCO3- 36 mmol/L
Mixed acid base disorders Metabolic alkalosis Respiratory acidosis

Diagnostic Indices of Metabolic Acidosis
1. Clinical setting : most important 2. Electrolyte battery (Na/K/Cl/total CO2) : screening test 1) serum Na :Cl ratio 2) serum anion gap (AG) 3. Serum osmolar gap (OG) 4. Δ AG : Δ HCO3- ratio 5. Fractional excretion of filtered anion (FEA; FEUA) 6. Urine H+ (ammonium) excretion in CD 1) urine net charge (anion gap) (UAG) 2) urine osmolar gap (UOG) 3) acid loading test 4) alkali loading test 5) morphological identification of H+-ATPase

Na+ Na : Cl Ratio = HCO3- Cl - Normal Cl
(ISE 140 : 105 – 110) 1. Increased Cl : decreased total CO2 (HCO3- or CO2) - metabolic acidosis, respiratory alkalosis 2. Decreased Cl : increased total CO2 (HCO3- or CO2) - metabolic alkalosis, respiratory acidosis

Anion Gap in Metabolic Acidosis
Normal AG AG Na+ Cl - Cl - Cl - = = = HCO3- HCO3- A- HCO3- A- A- Normal Acid Gain Alkali Loss

AG = [A-] = [Na+] – {[Cl-]+[HCO3-]}
Serum Anion Gap AG = [A-] = [Na+] – {[Cl-]+[HCO3-]} Normal : mmol/L (ISE : 3 – 11 mmol/L) 1. Normal AG metabolic acidosis - hyperchloremic metabolic acidosis - alkali loss 2. High AG metabolic acidosis - acid production (gain)

High AG acidosis Normal AG acidosis Lactic acidosis Diarrhea Ketoacidosis Isotonic saline infusion End-stage renal failure Early renal insufficiency Methanol ingestion Renal tubular acidosis Ethylene glycol ingestion Acetazolamide Salicylate toxicity Ureterenterostomy

Δ AG/ ∇ [HCO3-] Ratio (Gap to Gap)
Cell H+ Pr- Plasma A H+ Na+ HCO3- + H2O + CO2 Urine Na A <1 : High AG Metabolic acidosis + Normal AG metabolic acidosis ex) severe diarrhea + volume depletion related lactic acidosis 1 : DKA 1-2 : High AG Metabolic acidosis > 2 : Mixed disorder Metabolic acidosis with 1) metabolic alkalosis - increased [HCO3-] or albumin(A-) 2) respiratory acidosis - increased PCO2 AG excess/HCO3 Deficit = (AG-12)/(24-HCO3) High AG metabolic acidosis가 있다면, AG excess(정상 AG과 측정된 AG간의 차이)와 HCO3 deficit(정상 HCO3 농도와 측정된 HCO3 농도의 차이)을 비교함으로써 다른 대사성 산-염기 장애(예를 들면, normal AG metabolic acidosis이나 metabolic alkalosis)가 동시에 있는지 발견할 수 있다. AG excess/HCO3 deficit은 다음과 같이 계산할 수 있다(정상 AG는 12 mEq/L이고 정상 혈청 HCO3의 농도는 24 mEq/L이다). AG excess/HCO3 Deficit = (AG-12)/(24-HCO3) (22.15) 이 비율을 gap-gap 이라 부르는데 세포외액의 HCO3 농도변화와 다른 gap과의 차이(gap)를 측정하기 때문이다. 세포외액에 fixed acid(non-volatile acid)가 축척되면(예, high AG metabolic acidosis), 혈청 HCO3 감소는 AG 증가와 동일하기 때문에 AG excess/HCO3 deficit 비율은 1로 일정하다. 그러나 Normal AG metabolic acidosis이 동반되어 있으면 HCO3 감소가 AG 증가보다 크기 때문에 gap-gap 비율이 1이하로 떨어진다. a. 따라서 High AG metabolic acidosis가 있으면서 gap-gap<1이면, Normal AG metabolic acidosis이 동반되어 있다(5.14). 3. 대사성 산증과 알카리증(Metabolic Acidosis and Alkalosis) High AG metabolic acidosis에 알카리가 첨가되면, 혈청 HCO3 의 감소가 AG 증가보다 적게되므로 gap-gap 비율이 1이상으로 증가한다. a. 따라서 High AG metabolic acidosis이 있으면서 gap-gap>1이면, metabolic alkalosis가 동반되어 있다(5.14).

55-year-old Women with Severe Vomiting for 5 Days
Physical findings : postural hypotension, tachycardia, dry axilla Serum : [Na+] 140 mmol/L, [K+] 3.4 mmol/L, [Cl-] 77 mmol/L [HCO3-] 9 mmol/L AG 54 mmol/L ABGA : pH 7.23, PCO2 22 mmHg Δ AG 54 – 12 = : Δ [HCO3-] 24 – 9 = 15 Δ AG / Δ [HCO3-] = 42 / 15 = 2.8 Metabolic alkalosis (vomiting) + metabolic acidosis (lactic acidosis due to ischemia)

Serum Osmolar Gap Measured Osm = 2 [Na+] + Glucose + BUN + Unmeasured Osm Calculated Osm = 2 [Na+] + Glucose + BUN Osmolar gap (OG) = Unmeasured Osm (<10 mOsm/L) > 20 mOsm/L 1) Intoxication (methanol, ethanol, PEG) 2) Circulatory collapse, severe hypoxia, septic shock 3) Mannitol -

Evaluation of H+ Excretion in Collecting Duct
Urine ammonium excretion Acid loading (NH4Cl, CaCl2) test : urine pH <5.5 Furosemide test : urine pH <5.5 Alkali (NaHCO3) loading test - U-B PCO2 (difference in PCO2 from urine to blood) > 30 mmHg Morphological identification of H+-ATPase and AE-1

Na+ K + NH4 + Urine Electrolytes [Na+ + K+ + NH4+ ] = [ Cl- + A- ]
Urine AG (net charge) = [ Na+ + K+ - Cl- ] = - NH4+ + A- 집합관에서의 산배설을 반영 대사성 산증시는 요 산성화로 정상적으로는 -20~-50mmol/L Cl - Na+ K + = NH4 + A- Normal

Urine Ammonium (Acid) Excretion
1. Urine net charge (anion gap) : UAG UAG = Urine [Na+ + K+ + NH4+ - Cl-] Na+ + K+ + NH4+ = Cl- + A- NH4+ = - [Na+ + K+ - Cl-] + A- (< 0 mmol/L) 2. Urine osmolar gap : UOG Measured Osm = 2 [Na+ + K+ + NH4+] + Urea + Glucose Calculated Osm = 2 [Na+ + K+] Urea + Glucose Osmolar gap = 2 [NH4+] ( > 200 mmol/L) 100 mOsm/kgH2O 미만시 집합관장애 -

Urine anon gap (UAG) and osmolal gap (UOG) in CRF (solid circle)
and dRTA (triangle) patients and in NH4Cl-loaded normal controls ( Kim et al. Am J Kidney Dis 1996;(1):42-47)

Causes of Metabolic Acidosis
I. Acid gain (production) high AG > 14 (9) mmol/L 1. Endogenous normal OG lactic acidosis, DKA, ESRD 2. Exogenous high OG > 20 mOsm/L methanol, ethanol, ethylene glycol II. Alkali (HCO3- ) loss normal AG ; hyperchloremia 1. Direct loss (-) UAG; UOG > 200 1) GI loss : diarrhea 2) Renal loss : proximal RTA 2. Indirect loss (+) UAG ; UOG < 200 - defective HCO3- reclamation due to defective H+ excretion - distal RTA, hypoaldosteronism, mild CRF

Potassium in Metabolic Acidosis
Δ pH : Δ [K+] : ~ 1 mmol/L Hypokalemia in metabolic acidosis 1) diarrhea 2) renal tubular acidosis (Type I, II) 3) diabetic ketoacidosis

의식불명인 36세 알코홀 중독자 혈압 110/70 mmHg, 맥박 80회/분, 호흡 24회/분 혈청 : Na , K , Cl- 80, total CO mmol/L Glucose 90 mg/dL, BUN 14 mg/dL 동맥혈 : pH 7.29, P CO2 30 mmHg 이 환자의 혈청 음이온차는? 120 – [ ] = 25 mmol/L 2. 가장 먼저 시행할 검사는? 혈청 osmolality : 290 mOsm/Kg 3. 삼투질 농도차(osmolal gap)는? 290 – [2 x / /2.8] = 40 mOsm/Kg

혈청 : Na + 140, K + 2.5, Cl- 120, total CO2 15 mmol/L BUN 14 mg/dL
갑자기 생긴 하지마비가 있는 43세 주부 혈압 110/70 mmHg, 맥박 80회/분, 호흡 24회/분 혈청 : Na , K , Cl- 120, total CO mmol/L BUN 14 mg/dL 동맥혈 : pH 7.29, P CO2 30 mmHg 이 환자의 혈청 음이온차는? 140 – [ ] = 5 mmol/L 2. 가장 먼저 시행할 검사는? 요전해질 : Na + 110, K + 20, Cl mmol/L 요삼투질: 351 mOsm/kg , 요 glucose : 18 mg/dL, 요 UN : 28 mg/dL 3. 요 음이온차와 삼투질 농도차(osmolal gap)는? 요음이온차 : –120 = 10 mmol/L 요삼투질농도차 : 351-[2 X ( ) + 18/ /2.8] = 80 mOsm/kg

Treatment of Metabolic Acidosis
1. Chronic 1) Target : [HCO3- ] 15 mmol/L 2) NaHCO3 1 ~ 3 g/day, Shohl solution 2. Acute 1) pH > 7.2 : target : [HCO3- ] 15 mmol/L Required [HCO3- ] = 0.5 x BW x { 15 –[HCO3- ]} 2) pH < 7.2 or [HCO3- ] < 10 mmol/L Required [HCO3- ] = 0.5 x BW x {0.4 x PCO2 – [HCO3- ]}

pH 7.02, PCO2 20 mmHg, [HCO3- ] 5 mmol/L
1. Target : [HCO3- ] 15 mmol/L [H+] = 24 x = 32 nmol/L (pH 7.50) overshoot alkalosis 2. Target : pH = [H+] 63 nmol/L [H+] = 63 = 24 x [HCO3- ] = x PCO2 = X PCO2 20 15 PCO2 [HCO3- ] 24 63

Lactic acidosis

Lactic Acidosis Type A (deficit of oxygen)
Shock, Acute severe hypoxia Type B (Compromised metabolism of L-lactate without hypoxia) Drung Cyanide, Metformin, Linezolid, NRTI (reverse transcriptase inhibitor) Acetaminophen, epinephrine, propofol, nitroprusside Liver failure Propylene glycol lorazepam, diazepam,esmolol, nitroglycerine, phenytoin 등의 약물의 용해를 위해 사용하는 약물이다. Propylene glycol의 대사는 일차적으로 간에서 이루어지며 대사 산물로 젓산과 pyruvate가 형성

Bicarbonate Therapy in Lactic Acidosis
1. Conventional dose of bicarbonate therapy - no definite benefit on cardiac output and mortality - severe CV disease : depression of hemodynamics 2. Large dose of bicarbonate with concomitant dialysis - decrease mortality

Diabetic Ketoacidosis
- Harrison’s Principles of Internal Medicine, 15th eds.- Despite a bicarbonate deficit, bicarbonate replacement is not usually necessary or advisable. In fact, theoretical arguments suggest that bicarbonate administration and rapid reversal of acidosis may impair cardiac function, impair tissue oxygenation, and promote hypokalemia. The result of most clinical trials do not support the routine use of bicarbonate replacement. In the presence of severe acidosis (arterial pH<7.0 or hypotension unresponsive to fluid resuscitation), some physicians administer bicarbonate.

Alcoholic ketoacidosis
영양부족, 에탄올의 간에서의 산화(알콜에 의해 NADH 가 생성되어 β-hydroxybutyrate를 증가시킴), 탈수(소변으로 케톤산 배출이 저하됨)등의 여러 원인의 ketosis가 관계하는 복합질환 B. 임상 양상 1. AKA는 보통 만성 알코올 중독자에서, 과음하고1-3일 후에 발생 2. 임상 양상 : 오심, 구토, 복통 전해질 장애는 흔하며 특히 전반적인 저하증 (예, 저나트륨혈증, 저칼륨증, 저인산염증, 저마그네슘증, 저혈당 등). 3. AKA에서는 혼합 산-염기 장애가 흔하다. 반 이상의 환자에서 젓산증 (lactic acidosis)이 있으며(다른 원인으로 유발된) 지속적인 구토가 있는 환자는 대사성 알칼리증이 발생한다.

Alcoholic ketoacidosis
AKA는 과음을 한 병력과 함께 AG(anion gap)이 증가하고, 혈액과 소변내 케톤이 존재하면 확진한다. 2. AKA에서 β-hydroxybutyrate와 acetoacetate의 혈중 비는 8:1로 acetoacetate 의 혈중농도는 통상적인 검사법(nitroprusside반응)으로 검출이 안 될 정도 로 낮을 수 있다. 따라서, AKA에서 nitroprusside 반응으로 ketone을 검출하는 검사는 음성일 수 있다. 이럴 경우, AKA의 진단은 High AG metabolic acidosis 를 유발하는 다른 질환(예, lactic acidosis)을 배제시켜 나가야 할 수 있다. D. 처치 AKA는 포도당을 포함하는 생리식염수 IV로 교정할 수 있다. 포도당은 간에서의 ketone 생성을 억제하고, 주입된 수액은 소변으로의 케톤의 배출을 촉진한다. 케톤산증은 보통 24시간 내에 호전 될 수 있다.

Cardiac Arrest 1. Bicarbonate therapy in cardiac arrest over 30 years
improve acidemia believed cardiac function improvement 2. Recent data Increased myocardial CO2 tension  decreased pHi  decreased contractility bicarbonate therapy : increased CO2 tension little benefit in the success of cardiac resuscitation

Metabolic Disorders of Acid Base Balance

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