Biochemistry Departement Medical Faculty Of Andalas University ACID-BASE BALANCE By: Husnil Kadri Biochemistry Departement Medical Faculty Of Andalas University Padang

Hendersen-Hasselbalch (1909) CARA TRADISIONAL : Hendersen-Hasselbalch (1909)

BASA [HCO3-] GINJAL ASAM PARU Normal BASA [HCO3-] GINJAL pH = 6.1 + log Kompensasi  pCO2 CO2 Normal ASAM PARU CO2

Carbonic acid/bicarbonate buffer system pKa = 6.1 H2CO3  H+ + HCO3- ECF: Carbonic acid Bicarbonate ion The pKa of carbonic acid is 6.1 Carbonic acid is the major buffer in ECF The pH of blood can be determined using the Henderson-Hasselbalch equation

Henderson-Hasselbalch equation pH = pKa + log [HCO3-]/[H2CO3] pH = pKa + log [HCO3-]/0.03 x PCO2 7.4 = 6.1 + log 20 / 1 7.4 = 6.1 + 1.3 Plasma pH equals 7.4 when buffer ratio is 20/1 The solubility constant of CO2 is 0.03

GANGGUAN KESEIMBANGAN ASAM-BASA TRADISIONAL DISORDER pH PRIMER RESPON KOMPENSASI ASIDOSIS METABOLIK  HCO3-  pCO2  ALKALOSIS METABOLIK  HCO3-  pCO2  ASIDOSIS RESPIRATORI pCO2  ALKALOSIS RESPIRATORI pCO2  HCO3- 

Normal Compensatory Response Any primary disturbance in acid-base homeostasis invokes a normal compensatory response. A primary metabolic disorder leads to respiratory compensation, and a primary respiratory disorder leads to an acute metabolic response due to the buffering capacity of body fluids. A more chronic compensation (1-2 days) due to alterations in renal function.

Mixed Acid - Base Disorder Most acid-base disorders result from a single primary disturbance with the normal physiologic compensatory response and are called simple acid-base disorders. In certain cases, however, particularly in seriously ill patients, two or more different primary disorders may occur simultaneously, resulting in a mixed acid-base disorder. The net effect of mixed disorders may be additive (eg, metabolic acidosis and respiratory acidosis) and result in extreme alteration of pH; or they may be opposite (eg, metabolic acidosis and respiratory alkalosis) and nullify each other’s effects on the pH.

pH atau [H+] DALAM PLASMA DITENTUKAN OLEH Cara Stewart ; pH atau [H+] DALAM PLASMA DITENTUKAN OLEH DUA VARIABEL VARIABEL INDEPENDEN VARIABEL DEPENDEN Stewart PA. Can J Physiol Pharmacol 61:1444-1461, 1983.

INDEPENDENT VARIABLES Strong Ions Difference pH pCO2 Protein Concentration

VARIABEL INDEPENDEN CO2 STRONG ION DIFFERENCE WEAK ACID pCO2 SID Atot

DEPENDENT VARIABLES H+ HCO3- OH- AH CO3- A-

CO2 CO2 Didalam plasma berada dalam 4 bentuk sCO2 (terlarut) H2CO3 asam karbonat HCO3- ion bikarbonat CO32- ion karbonat Rx dominan dari CO2 adalah rx absorpsi OH- hasil disosiasi air dengan melepas H+. Semakin tinggi pCO2 semakin banyak H+ yang terbentuk. Ini yg menjadi dasar dari terminologi “respiratory acidosis,” yaitu pelepasan ion hidrogen akibat  pCO2

STRONG ION DIFFERENCE Definisi: Strong ion difference adalah ketidakseimbangan muatan dari ion-ion kuat. Lebih rinci lagi, SID adalah jumlah konsentrasi basa kation kuat dikurangi jumlah dari konsentrasi asam anion kuat. Untuk definisi ini semua konsentrasi ion-ion diekspresikan dalam ekuivalensi (mEq/L). Semua ion kuat akan terdisosiasi sempurna jika berada didalam larutan, misalnya ion natrium (Na+), atau klorida (Cl-). Karena selalu berdisosiasi ini maka ion-ion kuat tersebut tidak berpartisipasi dalam reaksi-reaksi kimia. Perannya dalam kimia asam basa hanya pada hubungan elektronetraliti.

STRONG ION DIFFERENCE SID KATION ANION Gamblegram Na+ 140 Mg++ Ca++ K+ 4 SID Na+ 140 Cl- 102 [Na+] + [K+] + [kation divalen] - [Cl-] - [asam organik kuat-] [Na+] + [K+] - [Cl-] = [SID] 140 mEq/L + 4 mEq/L - 102 mEq/L = 34 mEq/L KATION ANION

SKETSA HUBUNGAN ANTARA SID,H+ DAN OH- Konsentrasi [H+] Asidosis Alkalosis SID (–) (+) Dalam cairan biologis (plasma) dgn suhu 370C, SID hampir selalu positif, biasanya berkisar 30-40 mEq/Liter

WEAK ACID [Atot] (KA) = [A-].[H+] [Protein-] + [H+] [Protein H] disosiasi Kombinasi protein dan posfat disebut asam lemah total (total weak acid)  [Atot]. Reaksi disosiasinya adalah: [Atot] (KA) = [A-].[H+]

SID KATION ANION Gamblegram HCO3- 24 Na+ 140 Cl- 102 K+ 4 Weak acid Mg++ HCO3- 24 Ca++ K+ 4 SID Na+ 140 Weak acid (Alb-,P-) Cl- 102 KATION ANION

Asidosis hiperkloremi APLIKASI H3O+ = H+ = 40 mEq/L Na 140 K HCO3 = 24 HCO3-  HCO3-  HCO3-  Mg SID Ca SID n SID  Alb P Alb Cl 115 Laktat/keto=UA P Alb Cl 102 Cl 102 P CL 95 Keto/laktat asidosis Asidosis hiperkloremi Alkalosis hipokloremi KATION ANION

KLASIFIKASI GANGGUAN KESEIMBANGAN ASAM BASA BERDASARKAN PRINSIP STEWART Fencl V, Jabor A, Kazda A, Figge J. Diagnosis of metabolic acid-base disturbances in critically ill patients. Am J Respir Crit Care Med 2000 Dec;162(6):2246-51

KLASIFIKASI ASIDOSIS ALKALOSIS I. Respiratori  PCO2  PCO2   ASIDOSIS ALKALOSIS I. Respiratori  PCO2  PCO2 II. Nonrespiratori (metabolik) 1. Gangguan pd SID a. Kelebihan / kekurangan air  [Na+],  SID  [Na+],  SID b. Ketidakseimbangan anion kuat: i. Kelebihan / kekurangan Cl-  [Cl-],  SID  [Cl-],  SID ii. Ada anion tak terukur  [UA-],  SID 2. Gangguan pd asam lemah i. Kadar albumin  [Alb]  [Alb] ii. Kadar posphate  [Pi]  [Pi] Fencl V, Jabor A, Kazda A, Figge J. Diagnosis of metabolic acid-base disturbances in critically ill patients. Am J Respir Crit Care Med 2000 Dec;162(6):2246-51

Fencl V, Am J Respir Crit Care Med 2000 Dec;162(6):2246-51 RESPIRASI M E T A B O L I K Abnormal pCO2 Abnormal SID Abnormal Weak acid Alb PO4- AIR  Anion kuat Cl- UA- Turun Alkalosis Turun kekurangan Hipo Asidosis Meningkat kelebihan Hiper Positif meningkat Fencl V, Am J Respir Crit Care Med 2000 Dec;162(6):2246-51

KEKURANGAN AIR - WATER DEFICIT Diuretic Diabetes Insipidus Evaporasi Plasma Plasma Na+ = 140 mEq/L Cl- = 102 mEq/L SID = 38 mEq/L 140/1/2 = 280 mEq/L 102/1/2 = 204 mEq/L SID = 76 mEq/L 1 liter ½ liter SID : 38  76 = alkalosis ALKALOSIS KONTRAKSI

KELEBIHAN AIR - WATER EXCESS Plasma 140/2 = 70 mEq/L 102/2 = 51 mEq/L SID = 19 mEq/L Na+ = 140 mEq/L Cl- = 102 mEq/L SID = 38 mEq/L 1 Liter H2O 1 liter 2 liter SID : 38  19 = Acidosis ASIDOSIS DILUSI

GANGGUAN PD SID: Pengurangan Cl- ALKALOSIS HIPOKLOREMIK Plasma Na+ = 140 mEq/L Cl- = 95 mEq/L SID = 45 mEq/L 2 liter SID  ALKALOSIS ALKALOSIS HIPOKLOREMIK

GANGGUAN PD SID: Penambahan/akumulasi Cl- ASIDOSIS HIPERKLOREMIK Plasma Na+ = 140 mEq/L Cl- = 120 mEq/L SID = 20 mEq/L 2 liter SID  ASIDOSIS ASIDOSIS HIPERKLOREMIK

PLASMA + NaCl 0.9% SID : 38  Plasma NaCl 0.9% 1 liter 1 liter Na+ = 140 mEq/L Cl- = 102 mEq/L SID = 38 mEq/L Na+ = 154 mEq/L Cl- = 154 mEq/L SID = 0 mEq/L 1 liter 1 liter SID : 38 

ASIDOSIS HIPERKLOREMIK AKIBAT PEMBERIAN LARUTAN Na Cl 0.9% Plasma = Na+ = (140+154)/2 mEq/L= 147 mEq/L Cl- = (102+ 154)/2 mEq/L= 128 mEq/L 2 liter SID = 19 mEq/L SID : 19  Asidosis

PLASMA + Larutan RINGER LACTATE Laktat cepat dimetabolisme Ringer laktat Laktat cepat dimetabolisme Na+ = 140 mEq/L Cl- = 102 mEq/L SID= 38 mEq/L Cation+ = 137 mEq/L Cl- = 109 mEq/L Laktat- = 28 mEq/L SID = 0 mEq/L 1 liter 1 liter SID : 38

Normal pH setelah pemberian RINGER LACTATE Plasma = Na+ = (140+137)/2 mEq/L= 139 mEq/L Cl- = (102+ 109)/2 mEq/L = 105 mEq/L Laktat- (termetabolisme) = 0 mEq/L 2 liter SID = 34 mEq/L SID : 34  lebih alkalosis dibanding jika diberikan NaCl 0.9%

MEKANISME PEMBERIAN NA-BIKARBONAT PADA ASIDOSIS Plasma; asidosis hiperkloremik Plasma + NaHCO3 Na+ = 140 mEq/L Cl- = 130 mEq/L SID =10 mEq/L Na+ = 165 mEq/L Cl- = 130 mEq/L SID = 35 mEq/L 25 mEq NaHCO3 HCO3 cepat dimetabolisme 1 liter 1.025 liter SID  : 10  35 :  Alkalosis, pH kembali normal  namun mekanismenya bukan karena pemberian HCO3- melainkan karena pemberian Na+ tanpa anion kuat yg tidak dimetabolisme seperti Cl- sehingga SID   alkalosis

Laktat, acetoacetate, salisilat, metanol dll. UA = Unmeasured Anion: Laktat, acetoacetate, salisilat, metanol dll. Na+ K HCO3- Na+ K HCO3- SID  SID Keto- A- A- Cl- Cl- Lactic/Keto asidosis Normal Ketosis

GANGGUAN PD ASAM LEMAH: Hipo/Hiperalbumin- atau P- HCO3 Na HCO3 Na HCO3 K K K SID SID SID Alb-/P-  Alb-/P- Alb/P  Cl Cl Cl Asidosis hiperprotein/ hiperposfatemi Alkalosis hipoalbumin/hipoposfatemi Normal Acidosis Alkalosis

Anion Gap Described by Gamble in 1939 Electroneutrality Na+, Cl-, and HCO3 are measured ions Na + UC = Cl + HCO3 + UA UC = Sum of unmeasured cations UA = Sum of unmeasured anions The concept of an anion gap in blood was described in 1939 by Gamble. It was felt that the law of electroneutrality required that the number of positive charges contributed by serum cations should equal the number of negative charges contributed by serum anions. Sodium (Na), chloride (Cl), and bicarbonate (HCO3) are considered the measured ions. Potassium is ignored because its value changes so little. Thus, the concept of electroneutrality can be expressed by the simple equation: Na + UC = Cl + HCO3 + UA where UC (unmeasured cations) indicates the sum of the charges of the cations other than sodium and UA (unmeasured anions) equals the sum of the charges of all of the anions other than chloride and bicarbonate.

Anion Gap Unmeasured Cations: Unmeasured Anions: total 11 mEq/L Potassium 4 Calcium 5 Magnesium 2 Unmeasured Anions: total 23 mEq/L Sulfates 1 Phosphates 2 Albumin 16 Lactic acid 1 Org. acids 3 The “unmeasured cations” usually total about 11 mEq/L and include potassium (4 mEq/L), calcium (5 mEq/L), and magnesium (2 mEq/L). The “unmeasured” serum anions include sulfates (1 mEq/L), phosphates (2 mEq/L), proteins (16 mEq/L), lactic acid (1 mEq/L), and other organic acids (3 mEq/L). Ordinarily, the sodium concentration is about 140 mEq/L, and the sum of the CO2 content and chloride anions is about 128 mEq/L. Thus, the difference (or anion gap) between the sodium concentration and the sum of these two anions averages about 12 mEq/L. In patients with excessive acid production, the anion gap tends to be increased. On the other hand, in patients with metabolic acidosis due to loss of bicarbonate, the anion gap usually stays relatively normal.

Anion Gap = Na - (Cl + HCO3) Na + UC = Cl + HCO3 + UA 140 + 11 = 104 + 24 + 23 151 = 151 UA – UC = Na - (Cl + HCO3); Anion Gap = Na - (Cl + HCO3) The “unmeasured cations” usually total about 11 mEq/L and include potassium (4 mEq/L), calcium (5 mEq/L), and magnesium (2 mEq/L). The “unmeasured” serum anions include sulfates (1 mEq/L), phosphates (2 mEq/L), proteins (16 mEq/L), lactic acid (1 mEq/L), and other organic acids (3 mEq/L). Ordinarily, the sodium concentration is about 140 mEq/L, and the sum of the CO2 content and chloride anions is about 128 mEq/L. Thus, the difference (or anion gap) between the sodium concentration and the sum of these two anions averages about 12 mEq/L. In patients with excessive acid production, the anion gap tends to be increased. On the other hand, in patients with metabolic acidosis due to loss of bicarbonate, the anion gap usually stays relatively normal.

If the anion gap is elevated Then compare the changes from normal between the anion gap and [HCO3 -]. If the change in the anion gap is greater than the change in the [HCO3 -] from normal, then a metabolic alkalosis is present in addition to a gap metabolic acidosis. If the change in the anion gap is less than the change in the [HCO3 -] from normal, then a non gap metabolic acidosis is present in addition to a gap metabolic acidosis.

Anion Gap Acidosis: Anion gap >12 mEq/L; caused by a decrease in [HCO3 -] balanced by an increase in an unmeasured acid ion from either endogenous production or exogenous ingestion (normochloremic acidosis).

Non anion Gap Acidosis: Anion gap = 8-12 mmol/L; caused by a decrease in [HCO3 -] balanced by an increase in chloride (hyperchloremic acidosis). Renal tubular acidosis is a type of non gap acidosis

Increased Anion Gap Normal = 8-15 May differ institutionally Accumulation of organic acids (ketones, lactate) Toxic Ingestions methanol, ethylene glycol, salicylates Reduced inorganic acid excretion phosphates, sulfates Decrease in unmeasured cations (unusual) Lactate, Keto acids most common organic acids. AG> 35: M, EG, HHC, LA Toxic ingestions: Cyanide, ASA, M, EG, Par, Toluene Reduced Inorganic: Renal failure

Increased AG Metabolic Acidosis: Lactic Acidosis Has many etiologies Cyanide, CO, Toluene, HS Poor perfusion Ethylene glycol Salicylates Methyl salicylate (Oil of wintergreen) Mg salicylate Methanol Uremia/Renal Failure INH, Iron--lactate Paraldehyde Levraut J et al. Int Care Med 23:417, 1997

Increased Anion Gap Normal = 8-15 May differ institutionally “ion specific electrodes” Accumulation of organic acids (ketones, lactate) Toxic Ingestions methanol, ethylene glycol, salicylates Reduced inorganic acid excretion phosphates, sulfates Decrease in unmeasured cations (unusual) Excessive exposure to air: Increase Na, Cl, and K with decrease in bicarb secondary to loss of CO2. AG after 2 hours can be increased by 6 False elevation of CL: Hypertriglyceridemia, Bromide, Iodide Lactate, Keto acids most common organic acids. AG> 35: M, EG, HHC, LA Toxic ingestions: Cyanide, ASA, M, EG, Par, Toluene Reduced Inorganic: Renal failure

Decreased or Negative Anion Gap Clin J Am Soc Nephrol 2: 162-174, 2007 Low protein most important Albumin has many unmeasured negative charges “Normal” anion gap (12) in cachectic person Indicates anion gap metabolic acidosis Other etiologies of low AG: Low K, Mg, Ca, increased globulins (Mult. Myeloma), I intoxication Negative AG more unmeasured cations than unmeasured anions Bromide, Iodide, Multiple Myeloma

Change in Anion Gap vs HCO3 In simple AG Metabolic Acidosis decrease in plasma bicarbonate = increase in AG Anion Gap = 1 HCO3 Helpful in identifying mixed disorders In uncomplicated increased anion gap metabolic acidosis, the decrease (change) in plasma bicarbonate should be roughly equal to the increase (change) in the anion gap (that is, dAG/dHCO3 = 1.0). Whenever the anion gap changes much more or less than the bicarbonate, one should be suspicious of a coexisting or a mixed acid-base disorder. Ratios between 0.3 and 0.7 usually, but not always, indicate a mixed acid-base disorder or a preexisting low anion gap. Thus, the dAG/dHCO3 ratio is helpful in the diagnosis of mixed acid-base disorder because this ratio is usually close to 1.0 in typical organic acidoses. Values greater than 1.2 or less than 0.8 suggest the presence of a mixed acid-base disorder or an independent factor affecting the anion gap.

Respiratory Compensation for Metabolic Acidosis: Occurs rapidly Hyperventilation “Kussmaul Respirations” Deep > rapid (high tidal volume) Is not Respiratory Alkalosis Metabolic Alkalosis: Calculation not as accurate Hypoventilation Not Respiratory Acidosis Restricted by hypoxemia PCO2 seldom > 50-55 Commonly, compensation for a Pure metabolic Alkalosis: pCO2= 0.9 x HCO3 + 9 (not 15) pCO2 cannot go below 10 experimentally Resp. Compensation never raises the pH above 7.35

Reference Achmadi, A., George, YWH., Mustafa, I. Pendekatan “Stewart” Dalam Fisiologi Keseimbangan Asam Basa. 2007 Beaudoin, D. Electrolytes and ion sensitive electrodes. PPT. 2003. Ivkovic, A ., Dave, R. Renal review. PPT Kersten. Fluid and electrolytes. PPT. Marieb, EN. Fluid, electrolyte, and acid-base balance. PPT. Pearson Education, Inc. 2004 Rashid, FA. Respiratory mechanism in acid-base homeostasis. PPT. 2005. Silverthorn, DU. Integrative Physiology II: Fluid and Electrolyte Balance. Chapter 20, part B. Pearson Education, Inc. 2004 Smith, SW. Acid-Base Disorders. www.acid-base.com