Physiology 4.8 AcidBaseBalance Rabe

Physiology 4.8

November 25, 2011

Acid-Base Regulation

Dr. Milagros Rabe

I. II. III. IV. V. VI. VII. VIII. IX.

OUTLINE Definitions Types and Sources of Acid Acid Base Balance Regulation of Acid Base Balance Primary Acid-Base Disturbances Interpreting ABGs Compensatory Mechanism Anion Gap Simple vs. Mixed Acid-Base Balance

II. TYPES AND SOURCES OF ACIDS Volatile Acids: 

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Objectives: Review: Acids and Bases; Chemistry Review: Sources of acids in the body Give the significance of acid-base balance regulation Give the significance of buffers in the body Enumerate the buffer systems Explain the different compensatory responses to regulate acid-base balance Respiratory o Renal o Give the expected compensatory responses Predict the expected acid base problems and compensatory responses responses given clinical problems

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I. DEFINITIONS: CHEMISTRY   

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Non-Volatile Acids

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Acid: proton donor, eg. HCl  H  + Cl Base: proton acceptor, eg. HCO3  NH3 + CH3COO Strong acid vs. weak acid = complete vs slight dissociation in aqueous solution o Strong acids when put in an aqueous solution dissociate completely o Strong acid ↔ weak conjugate base +  Eg: HCl  H  + Cl  Conjugate base = usually anion o Strong base ↔ weak conjugate acid +  Eg: NaOH  Na  + OH  Conjugate acid = anion or cation -5 10  mol/L HCl = weak concentration of a strong acid 5 mol/L CH3COOH (acetic acid) = strong concentration of a weak acid

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I. DEFINITIONS

pH

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[H ]

= log (1/[H ]) Henderson-Hasselbach Equation o pH = pK1  + log [HCO3 ]/S x pCO2 = 6.1 + log [HCO 3 ] /0.03 x pCO 2 + o pK is the negative logarithm of [H ] at which half of the acid molecules are not dissociated and half are dissociated o S is the solubility constant of CO2 in plasma at 38°C + o Expresses H   concentration in pH units rather than in actual concentration o An increase in bicarbonate concentration causes the pH to rise → acid-base balance shift toward alkalosis acid-base balance o Increase in PCO2 causes the pH to decrease → acid-base shift toward acidosis o Bicarbonate concentration is regulated mainly by the kidneys, whereas PCO2 in ECF is controlled by the rate of respiration

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Source: mainly from metabolism of CHON- 80miliequivalent (Guyton) Phosphoric and sulfuric acids (diet = phosphoprotein and methionine) + o 50-70 mEq H  per day Intermediary metabolism (lactic and ketoacids) They are neutralized by buffers in the blood and tissues o Neutralized by bicarbonate produced by the kidneys They cannot be converted to CO2 and thus, are not released by the respiratory tract Renal excretion is the only mode of removing these acids.(Guyton) IV. ACID BASE BALANCE

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:because it has the potential to generate H +  after hydration with H2O (Berne and Levy) H2CO3; lung excretion Decarboxylation reactions in TCA cycle Basal conditions: 300L (13mol) CO2 / day + CO2 + H2O + HCO3 ↔ H2CO3 ↔ H  + H  + Hb ↔ HHb + o For every H2CO3 that dissociates, H  is buffered by BC or plasma HCO3  is produced o At any given pH, reduced blood (deoxyHb) has more HCO 3  than oxygenated blood When you break down glucose to produce ATP  CO2  and H2O is produced o CO2  is a volatile acid, it is carried as bicarbonate, dissolved or attached to hemoglobin to hemoglobin Volatile acid 

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[H ] = 40 nmol/L Normal pH = 7.35 – 7.35 – 7.45  7.45 Defenses: 1. Chemical buffers in blood (phosphate, bicarbonate, hemoglobin) 2. Changes in alveolar ventilation- removal of CO2( Guyton) + 3. Regulation of renal H  excretion and HCO3  reabsorption

Responses to acid-base disturbances  Immediate o Blood buffers  Short term o Respiratory compensation  Long term o Renal compensation

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Table 1. Blood Buffers Buffer type    e    t    a    n    o     b    r    a    c    i    B    e    t    a    n    o     b    r    a    c    i     b    n    o    N

Buffering capacity (%)

Plasma

35

Erythrocyte

18

Hemoglobin and oxyhemoglobin

35

Plasma proteins

7

Organic phosphate

3

Inorganic phosphate

2

* Note that Bicarbonate plays an important role in extracellular buffering while Phosphates have minimal role **In **In RBC(IC), Hb is the most i mportant buffer (Guyton) *** **bicarbonate buffer system is the most powerful extracellular buffer   in the  body. (Guyton) Tissue Buffers 

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Decreasing rate of respiration → lungs elevate PCO2 → increases + CO2 → increases H concentration in ECF (above normal) → respiratory system is stimulated → alveolar ventilation increases + → PCO2 in ECF decreases → reduces H   concentration back to normal + Increase [H ] or decreased pH stimulates central chemoreceptors (in the ventral surface of the medulla) and peripheral chemoreceptors (carotid and aortic bodies) to increase pulmonary ventilation Respiratory response to metabolic acid-base disturbances may be initiated within minutes but could require several hours to complete o

“Buffer Power” of system is determined by the amount and relative concentrations of the buffer components + Major buffer capacity of body are found in H  acceptors in tissues o Mainly muscle proteins  as this is most abundant tissue in body o Muscle cells have 12 mEq/L HCO3 o Bone carbonate  is 50 times more the amount of HCO 3 Phosphate Buffer System – System  – role  role in buffering renal tubular-fluid and intracellular fluids Tissues neutralize 5 times as much acid as blood b uffers Hemoglobin is the most important buffer in RBC Most of body buffers located in ICF, hemoglobin is in ICF

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Renal Regulation

 Although the kidneys are relatively slow to respond compared with the other defenses, over a period of hours to several days, they are by far the most powerful of the acid-base regulatory systems. (Guyton)  – kidneys Elimination of non-volatile acids – kidneys  –  most abundant weak acid waste o Acid phosphate (H 2PO4)  –  product of metabolism o Others: lactic acids and ketoacids Diet type influences non-volatile acid production that the kidneys eliminate o High protein diet  produces more sulfuric acid o Vegetarian diets  are associated with large intake of lactate and acetate o Half of metabolically produced acids are neutralized by base in the diet o Others buffered by anion systems of the body and by HCO3 o Various urinary buffers are termed titratable acids (Berne and Levy) 

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Excretion of H by the Kidneys

Unoxygenated Hb can bind with H and act as buffer(Guyton) pH of ECF can be controlled by the relative rate of removal and addition of bicarbonate and rate of removal of carbon dioxide

Arterial Blood Gases (Normal Values) **note: must know! So memorize!!  

pH = 7.4 ± 0.03 + [H ] = 40 ± 3 nmol/L pCO2 = 40 ± 5 mmHg [HCO 3 ] = 24 ± 4 mmol/L pH = 6.1 + log ([HCO 3 ] / 0.03 * pCO 2) + [H ] = 24 * (pCO 2 / [HCO3]) V. REGULATION OF ACID BASE BALANCE Respiratory regulation 

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CO2 transport o 90% as HCO 3 o 5% as carbaminohemoglobin o 5% as dissolved CO2 For every 10 mmHg rise in pCO2 above 40 mmHg, [HCO3 ] increases by 1 mEq/L pCO2 is inversely related to pulmonary ventilation o ↓pCO2, ↑respiration rate o The main stimulus for respiration is CO2 Short term regulation Regulates volatile acid elimination + Respiratory system acts as a negative feedback controller of H concentration

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CO2 is soluble across the plasma membrane For H to be reabsorbed, it must react with HCO3 forming H2CO3 Thus, the kidneys regulate extracellular fluid H+ H+ concentration through three fundamental mechanisms: (1) secretion of H + , (2 ) reabsorption of filtered HCO3 and (3 ) production of new HCO3 (Guyton).  

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Regulation of H  Secretion (Berne and Levy) + primary factor that regulates H  secretion by the nephron is a change in systemic acid-base balance HCO3  Reabsorption along the Nephron 

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proximal tubule reabsorbs the largest portion of the filtered load of HCO3 + H  is secreted into tubular fluid, whereas HCO3  exits the cell across the basolateral membrane and returns to the peritubular blood Via : + o 1Na  with 3HCO3 cotransporter + + Na -independent and/or Na -dependent Cl -HCO3 o antiporters o carbonic anhydrase in brush border of the PCT--> + (In the lumen)H2CO3---> HCO3 + H Production of New HCO3 Generation of new HCO3  is achieved by the excretion of titratable acid and by the synthesis and excretion of + NH4 . + NH4  is produced in the kidneys via the metabolism of glutamine 

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VII. COMPENSATORY MECHANISM 

V. PRIMARY ACID BASE DISTURBANCES 

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Metabolic acidosis o Primary decrease in plasma [HCO3 ] due to non-carbonic acid accumulation or [HCO3 ] loss in ECF Ex. Renal Tubular Acidosis,Diarrhea, Vomiting of Intestinal Content, Diabetes Mellitus, Ingestion of Acids, Chronic Renal Failure. (Guyton) Metabolic alkalosis + o Primary increase in plasma [HCO3 ] due to H  (non-carbonic acid) loss or [HCO3 ]gain in the ECF Ex. Administration of Diuretics (Except the Carbonic Anhydrase Inhibitors), Excess Aldosterone, Vomiting of Gastric Contents, Ingestion of Alkaline Drugs.( Guyton) o Due to acid loss in the stomach/kidney  Vomiting, nasogastric drainage  Loss of Cl   will decrease availability for renal reabsorption + with Na + o Note: excess aldosterone  will lead to K   depletion with alkalosis + + +  Aldosterone causes retention of Na   lose K   and H  metabolic alkalosis Respiratory acidosis o Decreased ventilation → retaining CO2 o Primary increase increase in pCO2 (alveolar hypoventilation) o Eg: sleeping pill overdose  will depress opioid receptors in the command center for respiration in the medulla  leading to retention of CO2 Respiratory alkalosis o Manifest as hyperventilation causing decrease in pCO2

VI. INTERPRETING ABGs 

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Look at the pH o Is the primary acidosis (low) or alkalosis (high)? Check the CO2 (respiratory indicator) o Is it less than 35 (alkalosis) or more than 45 (acidosis)? Check the HCO3 (metabolic indicator) o Is it less than 22 (acidosis) or more than 26 (alkalosis)? Which is primary disorder (respiratory or metabolic)? o If the pH is low (acidosis), then look to see if CO2  or HCO3 is acidosis (whichever is acidosis will be primary). o If the pH is high (alkalosis), then look to see if CO2  or HCO 3 is alkalosis

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If respiratory system is main problem  renal compensation o Kidneys excrete more H and reabsorb more HCO3   in respiratory acidosis, if pH is N but pCO 2 is increased then the problem is not acute and kidneys had time to compensate alkalosis  –   kidneys compensate by excreting more o In respiratory alkalosis – HCO3 If main problem is loss or gain of non-volatile acid -> problem is metabolic, compensation is through respiratory system o If low pH due to increase HCO3  loss or gain in non-volatile acid → by increasing ventilation to increase loss of CO2 o If high pH due to primary acid loss, then the pulmonary ventilation is decreased to retain CO2

Primary and Secondary Changes

When the primary disturbance is an alteration in blood PCO 2 , it is called a respiratory disorder. During respiratory acidosis, rise of PCO 2  increases total carbon dioxide and as a compensatory response, HCO 3 increases. Whereas decreasing PCO2, in the case of respiratory alkalosis, HCO 3   concentration is reduced. When an acid-base disorder results from a primary change in [HCO 3 ], it is called a metabolic disorder. In metabolic acidosis, there is decreased bicarbonate concentration resulting to the reduction of PCO 2. In metabolic alkalosis, increased bicarbonate concentration causes increased PCO 2 as compensation.

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Normal Compensatory Responses

**note: memorize! Important in knowing if compensation is adequate MAIN PROBLEM EXPECT Dec pCO2 by 1-1.3 mmHg for Metabolic acidosis Dec [HCO3] every 1 mmol/L dec [HCO3] Inc pCO2 by 0.6-0.7 mmHg for Metabolic alkalosis Inc [HCO3] every 1 mmol/L inc [HCO3] Acute respiratory Inc [HCO3] by 1 mmol/L for Inc pCO2 acidosis every 10 mmHg inc pCO2 Chronic respiratory Inc [HCO 3] by 3-3.5 mmol/L for Inc pCO2 acidosis every 10 mmHg inc pCO2 Acute respiratory Dec [HCO3] by 2 mmol/L for Dec pCO2 alkalosis every 10 mmHg dec pCO2 Chronic respiratory Dec [HCO3] by 4-5 mmol/L for Dec pCO2 alkalosis every 10 mmHg dec pCO2 

If predicted compensatory value is not the same it means there is more than one cause of acid base problems o Mixed acid base problem  or compensation is not adequate

VIII. ANION GAP 

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Anion gap is the difference between positively charged (cations) and negatively charged (anions) ions in blood + + Anion Gap = ([Na ] + [K ]) – ]) – ([Cl  ([Cl ] + [HCO 3 ] + + o But K  is mainly intracellular, so mainly [Na ] o Normal = 12 ± 2 mmol/L (8-15mmol/L in some books) 2+ 2+ o Normal AG due to presence of unmeasured cations (Ca , Mg , + K ) and unmeasured anions (plasma proteins, phosphate, sulphate)  Gap increases if unmeasured cations fall or unmeasured anions rise Only important for determining the potential reasons causes METABOLIC ACIDOSIS o Certain conditions with metabolic acidosis have a normal anion gap, some with high anion gap o AG > 12 mmol/L (high) = ketoacidosis   (DM, starvation, alcohol intoxication), lactic acidosis, pisoning (salicylates, ethylene glycol, ethanol, methanol), chronic renal failure o Normal AG = loss of HCO3   from GI tract/kidney (diarrhea, renal tubular acidosis, urinary obstruction, intake of NH4Cl, Addison’s disease, use of Carbonic Anhydrase inhibitors) Causes of anion gap acidosis: (Remember mUD PILES) 

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Uremia Diabetic Ketoacidosis Paraldehyde, phenformin Iron, isoniazid, inhalants Lactic Acidosis Ethylene glycol (alcoholic ketoacidosis) Salicylates, solvents, starvation

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Patient vomiting (primary H   loss) and also has pneumonia (CO2 retention) o Diabetic but has pneumonia o Patient with renal failure but is vomiting Check history, arterial blood gas values, use an acid base normogram o

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Case 1 A 44-year old moderately dehydrated man was admitted with a two day history of acute severe diarrhea. + + Electrolyte results (in mmol/L): Na   134, K   2.9, Cl   113, HCO3  16, Urea 12.3, Creatinine 0.30 mmol/L. Arterial Blood Gases: pH – pH – 7.31  7.31 = net acidemia  – 33 mmHg = low pCO2 – 33 pO2 not given HCO3 – 16  – 16 mmol/L = low (decline by 8, expect pco2 to go down by roughly 8)  – 2.1 mmol/L K – 2.1 What is the anion gap? = [Na=134]+[K=2.9]-[Cl=113]+[HCO [Na=134]+[K=2.9]-[Cl=113]+[HCO3= 16] = 136.9-129  –  normal (diarrhea = 7.9 or 8 mmol/L  –  (diarrhea is a condition that can show a normal anion gap) What is the patient’s acid base status? Low HCO3 and low pCO2  levels are seen in METABOLIC ACIDOSIS and RESPIRATORY ALKALOSIS BUT history shows patient had diarrhea (loss of HCO3) and moderate dehydration which will most likely cause METABOLIC ACIDOSIS 

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What happened? Diarrhea -> loss of HCO3, Na+ from still Dehydration (low blood volume) -> decreased renal perfusion -> retention of creatinine and urea (pre renal failure) = kidneys unable to produce as much HCO3, pH cannot be fully corrected in 2 days  

Was compensatory response adequate? The maximal amount of respiratory compensation takes 12- 24 hours to occur so sufficient time has elapsed o The expected PCO2 should be 1.3 mm Hg/ 1 mmol decline in HCO3 o Normal HCO3 = 24 +/- 4 mmHg o PCO2 = 40+/- mmHg Patient ABGs o PCO2 = 33mmHg: HCO3 = 16mmol/L o 24-26 = mmol Expected decline in PCO2 = 40-8 40-8 = 32 mmHg Compensation is ADEQUATE! 

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VIII. SIMPLE VS. MIXED ACID BASE PROBLEMS  

Simple acid base problem  = caused by one primary factor only Mixed disturbances  = due to more than one primary factor o Can be found in:  Patients with emphysema (CO2  retention) and with uncontrolled diabetes mellitus (ketoacidosis= more than one source of an acid)

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