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Patholphysiology of Acid base Balance
Primarily altered in metabolic disorders Altered by buffering Altered by renal compensation for respiratory disorders Metabolic component [ HCO3- ] pH = pKa+ + log α pCO2 Respiratory component Primarily altered in respiratory disorders Altered by respiratory compensation for metabolic disorders The result of the interplay between metabolic and respiratory components 1H+ Na+ EC:
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Buffering of Strong Acid added to Extracellular Fluid
Extracellular pH 7.4 7.1 6.9 6.7 240 200 6.7 160 Cellular (H+) nmol/l Cellular pH 120 6.9 80 7.1 40 7.4 7.7 40 80 120 200 (H+) nmol/l Buffering of Strong Acid added to Extracellular Fluid Compartment Contribution Time course Extracellular fluid Cells Bone and connective tissue 40% 50% 10% PCO2 HCO-3 Instantaneous Rapid Slow Min Hrs/days Physochemical buffering Respiratory Physiological regulation Renal
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Cell functions depending on regional pH
Plasma membrane function - Passive permeability to cations and anions - Active transport processes - Hormon receptor functions - Cell shape, motility and excitability - Endo- and exocytosis Mitocondrial function - Energy storage - ATP generation - Ammoniagenesis - Other enzyme activities Cytoplasmic function - Glycolysis - Glyconeogenesis - Cyclic nucleotid function - Function of actin and myosin - Cytoskeleton function - O2 affinity of hemoglobin Function of other organelles
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Metabolic Acidosis Acid excess Base loss
Exogen acids: -HCl (fe. arginin chlorid, NH4Cl ) -H2SO4 ( fe. Methionin) Incomplete fat oxidation: -diabetes mellitus (ketoacid) -starvation alcoholic ketoacidosis Incomplete carbohydrate oxidation: (lactic acidosis) -shock, diabetes cirrhosis -leukemia Failure of acid excretion: ARF, CRF Ingestion of toxic substances: - salicylate overdose, - methanol, ethylene glycol Gastrointestinal loss of HCO-3 - diarrhea - small- bowel or pancreatic fistula, drainage - ureterosigmoidostomy - anion exchange resins Renal loss of HCO-3 - carbonic anhydrase inhibitors - renal tubular acidosis (RTA) - hyperparathyroidism - hypoaldosteronism
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Metabolic acidosis Compensation
Buffering EC IC Bone Compensation Lung: hyperventillation pCO2 = 1,0 1,5* (HCO-3) (CO2 =34-31 mmHg mmol HCO-3) Kidney: total acid excretion = UNH4 *V+ UTA *V U HCO-3*V 1mmol/kg/day max. ca mmol/kg/day
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Laboratory of Metabolic Acidosis
pH , HCO-3 , pCO2 Se-K (ICK ECK: total – K ) Anion gap = Na+ + K+- Cl- - HCO-3 norm: mmol/l Na++ K++ Ca++ + Mg++ = Cl-+ HCO-3+ PO=/-4 + organic anions protein + SO- -4 ~ Ø Non measured anions (~ // mmol/l – albumin) AG : (strong acids buffering HCO other anions ) Increased acid formation -diabetic ketoacidosis -alcoholic lactic acidosis Toxic materials -salycilate -methanol -ethylen glycol Acid excretion -ARF, CRF AG : (HCO Cl- - reabsorption hypercloremia): Gastrointertinal loss: Renal loss -diarrhea etc. - Carbonic anhydrase inhibitors - pancreatic fistula - Renal tubular acidosis (RTA) - Hyperparathyroidism - Hyperaldosteronism
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Failure of Acid Excretion in Renal Disease
Daily acid load Diseased kidney Bone buffering Solute and water load per nephron Nephron population Filtered phosphate Buffering by ECF and intracellular buffers Proximal HCO3- reabsorption per nephron Ability to maintain or increase NH3 secretion Urinary buffer (phosphate) Distal HCO3- delivery Plasma HCO3- concentration Complete HCO3- reabsorption NH4 excretion Titratable acid excretion relative to degree of acidosis Urinary HCO3- leak Acid urine Net acid excretion
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Respiratory response to metabolic acidosis
Respiratory response to metabolic acidosis. The increase in (H+) produced by metabolic acidosis is sensed by chemoreceptors in the brainstem and ventilation is stimulated, reducing PCO2. Altough no units are shown on the time axis, this response is fully manifest in 1 to 3 hours, and the reduction in PCO2 induced is sustained until the bicarbonate deficit is repaired. During the recovery process, a similar delay occurs between correction of the acidosis and restoration of normal ventilation, resulting in a transient period of alkalemia.
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Causes of Lactic Acidosis
Clinically characterised by decrease in tissue oxigenation No clinical sign of decreased tissue oxigenation Systemic disorders or conditions -diabetes mellitus -liver failure -sepsis -malignancy -pregnancy Intoxication -Ethanol -Etlylenglycol -Strychnine Muscular hyperactivity -seizures -marathon running Cardiogenic shock Hypovolemic shock Septic shock Hypoxemia (O2 < 35mmHg) Anemia ATP NADH Venous constriction Arteriolar dilatation Myocordial contraction Congrestive Heart failure (pH ) lactate mortality If > 4 mmol /l
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Lactic Acidosis Increased lactic acid production
Decreased lactate metabolism H+ + lactate anion gap HCO3- Distal nephron delivery of lactate (if plasma lactate > 7 to 8 mmol/l) pH Distal nephron anion (lactate) delivery Na+ lacate- excretion Buffering (ECF + ICF) Renal NH3 production ECF volume Ventilation Difference in lumen negative potential Distal nephron Na+ avidity Renal H+ secretion Renal NH4+ excretion Renal TA excretion Generation of HCO3- Generation of HCO3- pCO2 Rise in pH toward normal
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Causes of Renal Tubular Acidosis
Distal Proximal Hypokalemic or normokalemic - Primary - Hypercalcemia - Nephrocalcinosis - Multiple myeloma - Hepatic cirrhosis - Lupus erythematosus - Amphotericin B - Lithium - Toluene - Renal transplant rejection - Medullary sponge kidney Hyperkalemic - Hypoaldosteronism - Obstructive nephropathy - Sickle cell nephropathy Primary Cystinosis Wilson’s disease Lead toxicity Cadmium toxicity Mercury toxicity Amyloidosis Multiple myeloma Nephrotic syndrome Early renal transplant injury Medullary cystic disease Outdated tetracycline
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Proximal Tubular Acidosis
Proximal tubules: HCO-3 reabsorption distal HCO-3 load (norm: 85%) urine HCO hypercloremic metabolic alkalosis urine : Na+ , K+ , H2O Hyponatremia, hypokalemia, hypovolemia
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HCO-3 Reabsorption (meq/L GFR) COMPLETE REABSORPTION
NORMAL 25 HCO-3 Reabsorption (meq/L GFR) COMPLETE REABSORPTION 20 PROXIMAL ( Type II) RTA 15 TRESHOLD Plasma (HCO-3) (meq/L) 15 20 25 Filtered load Proximal reabsorption Distal delivery Distal reabsorption Urinary excretion Norm: ~ 80%: ~ 20 15%: ~ 4-6 60% „4 ~ 6” „6” „8” „10” 15% pH pH pH 7.8 Bicarbonate titration curve and segmental nephron deliver and absorption in proximal (type II) RTA
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4 LUMEN 1 8 3 7 PROXIMAL TUBULE CELL 6 5 2 BLOOD K+ HCO3- H2CO3 CO2
Proximal RTA (type II): hypokalemic, hyperchloremic metabolic acidosis (in acidosis: net acid excretion = acid generated) HCO3- H2CO3 CO2 CAIV 4 LUMEN 1 H2O 8 CO2 ADP H+ OH- Pi 3 PROXIMAL TUBULE CELL 7 Na+ CAIII ATP ADP HCO3- Pi 6 5 2 BLOOD K+ Pathophysiology of proximal (type II) RTA. The possible causes of abnormal proximal acidification include defects in the luminal Na+-H+ antiporter (1); the basolateral Na+-HCO3- symporter (2); the intracellular (3) or luminal (4) carbonic anhydrases (CA); sodium permeability (5); the Na-K ATPase (6); the intracellular generation of ATP (7); or membrane recycling, metabolism, or trafficking (8).
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Pathophysiologic Mechanisms of Distal Renal
Tubular Acidosis Defect Mechanism Example Gradient or backleak Secretory Voltage-dependent Rate-dependent Hypoaldosteronism Inability to achieve or maintain a low urine pH due to backleak of H+ or H2CO3 Decrease in both force and rate (conductance) of the H+ pump system; acidification impaired under all conditions Failure to maintain a negative potential difference in the collecting duct lumen due to decreased sodium reabsorption Decreased rate of H+ secretion, but intact ability to achieve a low pH with an acid load (force intact) Probably a combination of voltage-dependent and rate-dependent defects and decreased ammonia production Amphotericin B Classic distal RTA Amiloride, obstructive nephropathy, sickle cell disease Interstitial nephropathy Hyporeninemic hypoaldosteronism
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3 LUMEN 1 DISTAL TUBULE 2 BLOOD
Classical Distal RTA (type I): hypokalemic, hyperchloremic metabolic acidosis (in urine: inappropriate acidification) NH3 NH4+ HPO4 H2PO4- (TA) H+ 3 LUMEN 1 ADP ATP Pi H2O DISTAL TUBULE OH- CA CO2 Cl- HCO3- 2 BLOOD Pathophysiology of classical distal (type I) RTA. The possible causes of abnormal intercalated cell acidification in the distal nephron include defects in the luminal proton-translocating ATPase (1), the basolateral HCO3-Cl- antiporter (2), or luminal hydrogen ion permeability (3). TA, titratable acid; CA, carbonic anhydrase.
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Metabolic alkalosis Buffering ( IC+EC) HCO3+ + H+ CO2+H2O
Netto H+ loss (vomiting hyperaldosteronism) Netto HCO-3 increase (milk-alkali syndrome, baking powder) Cl- loss>HCO-3 loss (diureticum) Buffering ( IC+EC) HCO3+ + H CO2+H2O Compensation Pulmonary : hypoventillation Max. pCO2 ~ 60 mmHg Kidney: HCO3- secretion Maintaining factors: 1. Hypocloremia prox. tub. HCO-3 – reabs. 2. Hypokalemia „paradox aciduria” 3. Hypovolemia 4. Hyperaldosteronism ΔpCO2= * Δ HCO-3 (Fe: pCO mmHg mmol/l (HCO-3)
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MAINTENANCE OF METABOLIC ALKALOSIS
NASOGASTRIC SUCTION REMOVAL OF WATER SODIUM HYDROGEN ION CHLORIDE POTASSIUM PLASMA HCO3- pH PLASMA AND FILTERED Cl- ECF VOLUME H+ SHIFTS INTO ECF K+ SHIFTS INTO CELLS ALDOSTERONE FILTERED HCO3- HYPOVENTILATION PaCO2 K+ EXCRETION HYPOKALEMIA HCO3- ” REABSORPTION” MAINTENANCE OF METABOLIC ALKALOSIS
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NaCl-sensitive metabolic alkalosis (f.e.: vomiting)
ECV HCO3- reabsorption Low [Cl-] NaCl Na+ reabsorption Urine Cl- < 10 mmol/l Alkalosis + (priority of volumen regulation over the pH)
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NaCl resistant metabolic alkalosis (f.e.: glycocorticoid therapy)
ECV H+, K+ excretion HCO3- reabsorption Diastalis Na+ reabsorption NaCl Proximalis NaCl reabsorption Alkalosis
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Differential Diagnosis of Metabolic Alkalosis
Sodium chloride-responsive (UCl- <10 mmoles/L) Gastrointestinal disorders Vomiting Gastric drainage Villous adenoma of the colon Chloride diarrhea Diuretic therapy Correction of chronic hypercapnia Cystic fibrosis Sodium chloride-resistant (UCl- < 20 mmoles/L) Excess mineralocorticoid activity Hyperaldosteronism Cushing’s syndrome Bartter’s syndrome Excessive licorice intake Profound potassium depletion Unclassified Alkali administration Recovery from organic acidosis Antacids and exchange resins in renal failure Milk-alkali syndrome Massive blood or Plasmanate transfusion Nonparathyroid hypercalcemia Glucose ingestion after starvation Large doses of carbenicillin or penicillin
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Causes of Acute Respiratory Acidosis
Neuromuscular abnormalities Brain stem injury High cord injury Guillain-Barré syndrome Myasthenia gravis Botulism Narcotic, sedative, or tranquilizer overdose Airway obstruction Foreign body Aspiration of vomitus Laryngeal edema Severe bronchospasm Thoracic-pulmonary disorders Flail chest Pneumothorax Severe pneumonia Smoke inhalation Severe pulmonary edema Vascular disease Massive pulmonary embolism Respirator-controlled ventilation Inadequate frequency, tidal volume settings Large dead space Total parenteral nutrition (increased CO production)
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Acute Respiratory Acidosis
pCO2 ; pH ; pO2 ; act. HCO3 ; st. HCO3 [HCO3-] = (pCO2/10)3 (f.e.: [HCO3-] mmol/l pCO2 70 mmHg (12-24 ))
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Causes of Chronic Respiratory Acidosis
Neuromuscular abnormalities Chronic narcotic or sedative ingestion Primary hypoventilation Pickwickian syndrome Poliomyelitis Diaphragmatic paralysis Thoracic-pulmonary disorders Chronic obstructive airway disease Kyphoscoliosis End-stage interstitial pulmonary disease Laboratory pCO2 ; pH ; pO2 ; act. HCO3 ; st. HCO3- [HCO3] = 4x pCO2/10 4 (f.e.: [HCO3] mmol/l pCO2 70 mmHg)
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Respiratory acidosis H2CO3 AND pH EFFECTIVE ALVEOLAR VENTILATION
CO2 EXCRETION PaCO2 RENAL H+ SECRETION NH4 EXCRETION BALANCED BY Cl- EXCRETION INTRACELLULAR BUFFERS CONSUME H+ NET ACID EXCRETION HCO3 – RECLAMATION AND GENERATION PLASMA HCO CONCENTRATION APPROPRIATELY DEFENDED CHRONIC RESPIRATORY ACIDOSIS
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Figure: Schematic time course of the changes in plasma acid-base
Figure: Schematic time course of the changes in plasma acid-base equilibrium during the development of respiratory acidosis.
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Causes of Respiratory Alkalosis
Central stimulation of respiration Anxiety Head trauma Brain tumors or vascular accidents Salicylates Fever Pain Pregnancy Peripheral stimulation of respiration Pulmonary emboli Congestive heart failure Interstitial lung diseases Pneumonia „Stiff lungs” without hypoxemia Altitude Uncertain Hepatic insufficiency Gram-negative septicemia Mechanical or voluntary hyperventilation
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Respiratory Alkalosis
Acute: [HCO3 -] = 1-3x (pCO2/10) (f.e.: [HCO3 -] mmHg pCO2 30 mmHg) Chronic: [HCO3 -] = 2-5x (pCO2/10) (f.e.: [HCO3 -] mmHg pCO2 30 mmHg)
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Respiratory alkalosis
ALVEOLAR VENTILATION CO2 EXCRETION PaCO2 RENAL H+ SECRETION ECF pH HCO3 RECLAMATION NH4 EXCRETION TA EXCRETION INTRACELLULAR BUFFERS ADD H+ TO ECF BICARBONATURIA NET ACID EXCRETION Na+ K+ EXCRETION PLASMA HCO3 - CONCENTRATION Acute respiratory alkalosis [HCO3-]= 1-3x (pCO2/10) (f.e.: pCO2: 30 mmHg [HCO3-]: mmol/l) Chronic respiratory alkalosis [HCO3-]= 2-5x (pCO2/10) (f.e.: pCO2: 30 mmHg [HCO3-]: mmol/l)
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Normal or slightly or
Mixed Acid-Base Disorders Disorders Compensation pH Type 1: Failure of compensation PaCO2 too high and [HCO3-] too low for simple disorders Metabolic acidosis and respiratory alkalosis Metabolic alkalosis and respiratory alkalosis PaCO2 too low and [HCO3-] too high for simple disorders Type 2: Excessive compensation PaCO2 too low and [HCO3-] too low for simple disorders Normal or slightly or PaCO2 too high and [HCO3-] too high for simple disorders Normal or slightly or
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Example of a Triple Acid-Base Disorder
Clinical event Acid-base disorder pH PaCO2 (mm Hg) [HCO3-] (mmoles/l) Anion gap (mEq/L) Vomiting Metabolic alkalosis 7.53 44 36 14 Hypovolemic shock Metabolic acidosis 7.35 30 16 32 Hyperventilation Respiratory alkalosis 7.46 20 14 34
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