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Acid-Base Basic definitions An acid –a substance that can donate hydrogen ions (H + ) A base –a substance that can accept H + ions H 2 CO 3 (acid)«H +

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Presentation on theme: "Acid-Base Basic definitions An acid –a substance that can donate hydrogen ions (H + ) A base –a substance that can accept H + ions H 2 CO 3 (acid)«H +"— Presentation transcript:

1 Acid-Base Basic definitions An acid –a substance that can donate hydrogen ions (H + ) A base –a substance that can accept H + ions H 2 CO 3 (acid)«H + + HCO 3 - (base) Strong acids –completely ionized in body fluids Weak acids –incompletely ionized in body fluids

2 Acid-Base Basic definitions HCl«H + + Cl - –Hydrochloric acid (HCl) –a strong acid - it is present only in a completely ionized form in the body H 2 CO 3 (acid)«H + + HCO 3 - (base) –a weak acid - it is ionized incompletely –at equilibrium, all 3 reactants are present in body fluids

3 Acid-Base Basic definitions H 2 CO 3 (acid) « H + + HCO 3 - (base) the law of mass action - the velocity of a reaction is proportional to the product of the reactant concentrations   …………………………………………….  the addition of H + or bicarbonate (HCO 3 - ) drives this reaction to the left

4 Acid-Base Basic definitions in body fluids the concentration of hydrogen ions - H + –normal physiologic concentration = 40 nEq/L –is maintained within very narrow limits the concentration of HCO 3 - = (24 mEq/L) –is 600,000 times that of [H + ]

5 Acid-Base Basic definitions the tight regulation of [H + ] at this low concentration is crucial for normal cellular activities H + at higher concentrations can bind strongly to negatively charged proteins, including enzymes, and impair their function (!!) under normal conditions, acids and bases are being added constantly to the extracellular fluid compartment for the body to maintain a physiologic [H + ] of 40 mEq/L, 3 processes must take place: 1.Buffering by extracellular and intracellular buffers 2.Alveolar ventilation, which controls PaCO 2 3.Renal H + excretion, which controls plasma [HCO 3 - ]

6 Acid-Base

7 Buffers weak acids or bases that are able to minimize changes in pH –by taking up H + –by releasing H + Phosphate - effective buffer HPO (H + )«H 2 PO 4 - upon addition of an H + to extracellular fluids, the monohydrogen phosphate binds H + to form dihydrogen phosphate, minimizing the change in pH when [H + ] is decreased, the reaction is shifted to the left Thus, buffers work as –a first-line of defense (!!) –to blunt the changes in pH that would result from the constant daily addition of acids and bases to body fluids

8 Acid-Base Buffers HCO 3 - /H 2 CO 3 buffering system H 2 O + CO 2 «H 2 CO 3 «H + + HCO 3 the major extracellular buffering system a very effective system –has the ability to control PaCO 2 by changes in ventilation increased carbon dioxide (CO 2 ) concentration drives the reaction to the right, a decrease in CO 2 concentration drives it to the left H + added to the body fluids  formation of carbonic acid = consumption of HCO 3 carbonic acid (H 2 CO 3 )  water + CO 2  ventilation CO 2 concentration is maintained within a narrow range via the respiratory drive, which eliminates accumulating CO 2 the kidneys regenerate the HCO 3 - consumed during this reaction

9 Acid-Base Buffers H 2 O + CO 2 «H 2 CO 3 «H + + HCO 3 this reaction continues to move to the left –as long as CO2 is constantly eliminated –or until HCO3 - is significantly depleted, making less HCO3 - available to bind H+ HCO3 - and PaCO2 can be managed independently –HCO3 in the kidneys –PaCO2 in the lungs that makes this a very effective buffering system

10 Acid-Base Buffers HCO 3 - /H 2 CO 3 buffering system H 2 O + CO 2 «H 2 CO 3 «H + + HCO 3 Henderson-Hasselbalch equation –pH = log ([HCO3 -]/0.03 X PaCO2) –expresses the relationship between the 3 reactants in the reaction at equilibrium –an alternative - [H+] = 24 X PaCO2/[HCO3 -] Henderson-Hasselbalch equation relates: –dissolved CO2 (ie, H2 CO3) –to the partial pressure of CO2 (0.03 X PaCO2)

11 Acid-Base Buffers pH = log ([HCO3 -]/0.03 X PaCO2) changes in pH or [H + ] are a result of relative changes in the ratio of PaCO 2 to [HCO3 - ] rather than to absolute change in either one if both PaCO2 and [HCO3 - ] change in the same direction, the ratio stays the same and the pH or [H + ] remains relatively stable the alteration in pH occurs when either HCO3 - or PaCO2 changes the other variable in the same direction

12 Acid-Base Buffers intracellular buffers - hemoglobin, bone in chronic metabolic acidosis extracellular HCO 3 level is low intracellular buffers are more important than HCO 3

13 Acid-Base Renal acid handling Acids are added daily to the body fluids volatile acids - carbonic acid –the metabolism of dietary carbohydrates and fat produces approximately 15,000 mmol of CO 2 per day, which is excreted by the lungs –failure to do so results in respiratory acidosis nonvolatile - eg, sulfuric, phosphoric acids –the metabolism of proteins (ie, sulfur-containing amino acids) results in the formation of H2 SO4 –dietary phosphate results in the formation of H 3 PO 4

14 Acid-Base Renal acid handling these acids first are buffered by the HCO 3 -/H 2 CO 3 system: H 2 SO 4 + 2NaHCO 3 «Na 2 SO 4 + 2H 2 CO 3 «2H 2 O + CO 2 a strong acid (H 2 SO 4 ) is buffering by 2 molecules of HCO 3  a weak acid (H 2 CO 3 ) is produced  this minimizes the change in pH the lungs excrete the CO 2 produced the kidneys replace the consumed HCO3 –to prevent progressive HCO3 - loss and metabolic acidosis –kidneys perform these principally by H + secretion in the collecting duct

15 Acid-Base Renal acid handling prevention of metabolic acidosis  prevention of progressive HCO3 loss –amino acids ( glutamate, aspartate)  formation of citrate and lactate    convertion to HCO3 –to maintain normal pH, the kidneys must “reabsorb” all the filtered HCO3 - (any loss of HCO3 - is equal to the addition of an equimolar amount of H+) (in the proximal tubule) excrete the daily H+ load (loss of H+ is equal to addition of an equimolar amount of HCO3 -) (in the collecting duct)

16 Acid-Base Renal acid handling / HCO3 - reabsorption the daily glomerular ultrafiltrate in a healthy subject, contains 4300 mEq of HCO 3 – for –a serum HCO3 - concentration of 24 mEq/L –a daily glomerular ultrafiltrate of 180 L all of filtered HCO3 – has to be reabsorbed –90% in the proximal tubule, –the remainder in the thick ascending limb and the medullary collecting duct the energy for this process  the 3Na+ -2K+ «ATPase –maintains a low intracellular Na+ concentration and a relative negative intracellular potential  indirectly provides energy for the apical Na+/H+ exchanger - NHE3 (gene symbol SLC9A3)  transports H+ into the tubular lumen  H+ in the tubular lumen combines with filtered HCO3 – HCO3 - + H + «H2 CO3 «H2 O + CO2

17 Acid-Base Renal acid handling / HCO3 - reabsorption HCO3 - + H + «H2 CO3 «H2 O + CO2 the dissociation of H 2 CO 3 into H 2 O + CO 2 is accelerated by Carbonic anhydrase (CA IV isoform) –present in the brush border of the first 2 segments of the proximal tubule –this shifts the reaction shown above to the right and keeps the luminal concentration of H+ low CO2 diffuses into the proximal tubular cell, via the aquaporin-1 water channel carbonic anhydrase (CA II isoform) combines CO2 and water to form HCO3 - and H+ the HCO3 - formed intracellularly returns to the pericellular space and then to the circulation via the basolateral Na+/3HCO3 - cotransporter, NBCe1-A (gene symbol SLC4A4)

18 Acid-Base Renal acid handling / HCO3 - reabsorption In essence the filtered HCO3 - is converted to CO2 in the lumen CO2 diffuses into the proximal tubular cell in the tubular cell CO 2 is converted back to HCO3 – HCO3 – is returned to the systemic circulation in this way the filtered HCO3 – is recuperated

19 Acid-Base Renal acid handling Acid excretion the daily acid load = mEq of H+is excreted –through H+ secretion –by the apical H+ «ATPase –in A-type intercalated cells of the collecting duct

20 Acid-Base Renal acid handling / Acid excretion HCO3 - formed intracellularly is returned to the systemic circulation via the basolateral Cl - /HCO3 - exchanger, AE1 (gene symbol SLC4A1) H+ enters the tubular lumen via 1 of 2 apical proton pumps, H+ «ATPase or H+ - K+ «ATPase The secretion of H+ in these segments is influenced by Na+ reabsorption in the adjacent principal cells of the collecting duct –The reabsorbed Na+ creates a relative lumen negativity, which decreases the amount of secreted H+ that back-diffuses from the lumen

21 Acid-Base Renal acid handling / Acid excretion Hydrogen ions secreted by the kidneys can be excreted –as free ions –> 99.9% of the H + load - buffered by the weak bases NH3 or phosphate The reason for limited excretion of free H+ ions – the lowest achievable urine pH = 5.0 – = 10 µEq/L H+ – would require excretion of 5,000-10,000 L of urine a day –urine pH cannot be lowered much below 5.0 because the gradient against which H+ «ATPase has to pump protons (intracellular pH 7.5 to luminal pH 5) becomes too steep

22 Acid-Base Renal acid handling / urine-buffering system titratable acidity –the amount of secreted H+ that is buffered by filtered weak acids is called titratable acidity buffers in this system –phosphate as HPO4 2 –ammonia (NH3) –uric acid –creatinine H 2 PO 4 «H + + HPO 4 2- –the amount of phosphate filtered is limited and relatively fixed  only a fraction of the secreted H + can be buffered by HPO 4 2-

23 Acid-Base Renal acid handling / urine-buffering system / ammonia Ammonia NH 3 + H + «NH 4 + ammonia is produced in the proximal tubule from the amino acid glutamine this reaction is enhanced by –an acid load –hypokalemia

24 Acid-Base Renal acid handling / urine-buffering system / ammonia Intracellular - proximal tubules –NH 3 + H + «NH 4 + –NH 4 + is secreted into the proximal tubular lumen by the apical Na+/H+ (NH4 +) antiporter Intraluminal - thick ascending limb of the loop of Henle –the apical Na+/K+ (NH4 +)/2Cl- cotransporter in the thick ascending limb of the loop of Henle then transports NH4 + into the medullary interstitium –it dissociates back into NH3 and H+ –NH3 diffuses into the lumen of the collecting duct - available to buffer H+ ions and becomes NH4 +. –NH4 + is trapped in the lumen and excreted as the Cl salt.

25 Acid-Base Renal acid handling / urine-buffering system NH 3 + H + «NH 4 + the increased secretion of H + in the collecting duct  shifts the equation to the right  decreases the NH 3 concentration  facilitates continued diffusion of NH 3 from the interstitium down its concentration gradient  allows more H + to be buffered the kidneys and the liver can adjust the amount of NH 3 synthesized to meet demand, making this a powerful system to buffer secreted H + in the urine

26 Acid-Base Renal acid handling / urine-buffering system every H + ion buffered   an HCO 3 - gained to the systemic circulation

27 Echilibrul acidobazic – apărarea împotriva schimbării concetraţiei ionilor de H + Intervenţia rinichiului în condiţii de normalitate Relaţia [H + ] [NaHCO 3 - ] la ph normal al mediului intern Filtrare glomerulară NaHCO 3 - H + + CO 3 - H 2 CO 3 Celulă tub proximal Na+ CO 2 + H 2 O eliminată H 2 CO 3 Anhidraza carbonică HCO H + Cantitate redusă, aciditatea urinii Lichid extracelular Na+ Transport activ contraschimb CO2 (rezultat din metabolism) HCO 3 - Na HCO 3 Na+ HCO 3 - Lumen tubular CO 2 + H 2 O

28 Echilibrul acidobazic – apărarea împotriva schimbării concetraţiei ionilor de H + Intervenţia rinichiului în acidoză sistemul tampon fosfaţi H 2 PO 4 - Na + Lichid extracelular Filtrare glomerulară a Na 2 HPO 4 Na 2 HPO 4 Lumen tubular HPO 4 2- Celulă tub proximal Na + H 2 CO 3 CO2 CO2 + H2O HCO 3 - H + AC HCO 3 - Na + eliminare NaHCO 3 -

29 Echilibrul acidobazic – apărarea împotriva schimbării concetraţiei ionilor de H + Intervenţia rinichiului în acidoză Formarea amoniacului din glutamină Lumen tubular NH 4 Cl (acid slab) Na + Cl - Filtrare glomerulară a NaCl Na + Celulă tub proximalLichid extracelular Na+ Na H CO 3 HCO3- H 2 CO 3 HCO 3 - H + CO 2 + H 2 OCO 2 AC H+H+ eliminare glutamină NH 3

30 Echilibrul acidobazic – apărarea împotriva schimbării concetraţiei ionilor de H + Din catobolismul normal al proteinelor în ficat rezultă amoniac bicarbonat Din amoniac se formează uree Funcţie de necesităţi, o parte din amoniac este transformată în glutamină acidoza stimulează alcaloza inhibă Glutamina trece în circulaţie şi ajunge la nivelul celulei tubulare renale Dezaminarea glutaminei la nivelul celulei tubulare determină refacerea de HCO 3 - acidoza stimulează alcaloza inhibă Acidoza favorizează eliminarea urinară a NH 4 + şi se evită transformarea lui în uree care privează de regenerarea HCO 3 -

31 Echilibrul acidobazic – apărarea împotriva schimbării concetraţiei ionilor de H + Intervenţia rinichiului în acidoză Formarea amoniacului din glutamină H+H+ Lumen tubular NH 4 Cl (acid slab) Na + Cl - Filtrare glomerulară a NaCl Na + Celulă tub proximalLichid extracelular Na+ Na H CO 3 HCO3- H 2 CO 3 HCO 3 - H + CO 2 + H 2 OCO 2 AC eliminare glutamină NH 3 Eliminarea urinară de amoniu normal - 30 mmol/24 ore la nevoie - până la 300 mmol/zi

32 Echilibrul acidobazic – apărarea împotriva schimbării concetraţiei ionilor de H + Intervenţia rinichiului / factori perturbatori, de reglare funcţie de necesităţi/ Ph-ul mediului intern Lumen tubular Na + Cl - Filtrare glomerulară a NaCl Cl - Celulă tub distalLichid extracelular CL - H 2 CO 3 H + HCO 3 - CO 2 + H 2 O Alcaloză hipercloremică CO 2 AC HCO 3 - Na + NaHCO 3

33 Echilibrul acidobazic – apărarea împotriva schimbării concetraţiei ionilor de H +

34 Acid-Base Metabolic acidosis / Pathophysiology In healthy people blood pH is maintained at pH is the negative logarithm of [H+] (pH = - log10 [H+]) an increase in pH indicates a decrease in [H+] and vice versa an increase in [H+] and a fall in pH is termed acidemia a decrease in [H+] and an increase in pH is termed alkalemia the underlying disorders that lead to acidemia and alkalemia are acidosis and alkalosis, respectively metabolic acidosis is a primary decrease in serum HCO3 - concentration and, in its pure form, manifests as acidemia (pH <7.40)

35 Acid-Base Metabolic acidosis / Pathophysiology rarely, metabolic acidosis can be part of a mixed or complex acid-base disturbance 2 or more separate metabolic or respiratory derangements occur together  pH may not be reduced  or the HCO 3 - concentration may not be low

36 Acid-Base Metabolic acidosis / Pathophysiology compensatory mechanism = alveolar hyperventilation  a fall in PaCO2 normally, PaCO2 falls by mm Hg for every 1-mEq/L fall in serum HCO 3 - compensatory response that can occur fairly quickly change in PaCO2 not within this range = a mixed acid-base disturbance –ex, if the a less decrease in PaCO2 than the expected change = a primary respiratory acidosis also present

37 Acid-Base Metabolic acidosis / Pathophysiology often the first clue to metabolic acidosis is a decreased serum HCO3 - concentration observed when serum electrolytes are measured remember, however, that a decreased serum [HCO3 -] level can be observed as a compensatory response to respiratory alkalosis an [HCO 3 - ] level less than 15 mEq/L, however, almost always is due, at least in part, to metabolic acidosis

38 Acid-Base Metabolic acidosis / Anion gap plasma, like any other body fluid compartment, is neutral - total anions match total cations the major plasma cation is Na+ the major plasma anions are Cl- and HCO 3 – in lower concentrations –other cations: K+, Mg2+, and Ca2+ –other anions: phosphate, sulfate, and some organic anions

39 Acid-Base Metabolic acidosis / Anion gap the anion gap (AG) = the difference between –the concentration of the major measured cation Na + (140 mEq/L) and the major measured anions Cl - (108 mEq/L) and HCO 3 – (24 mEq/L) the gap is usually between 6 and 12 mEq/L

40 Acid-Base Metabolic acidosis / Anion gap the AG represents the difference between unmeasured anions and unmeasured cations: AG = [Na+]-([Cl-] + [HCO3 -]) = unmeasured anions - unmeasured cations an increase in the AG can result from: –a decrease in unmeasured cations: hypokalemia, hypocalcemia, hypomagnesemia –or an increase in unmeasured anions: hyperphosphatemia, high albumin levels in certain forms of metabolic acidosis, other anions accumulate by recognizing the increasing AG  a differential diagnosis for the cause of acidosis

41 Horacio J. Andorgué & Nicolaos E. Midias

42 Acid-Base Metabolic acidosis / Urinary AG helpful in evaluating some cases of non-AG metabolic acidosis –the major measured urinary cations: Na +, K + –the major measured urinary anion is Cl - Urine AG = ([Na+] + [K+]) - [Cl-] the major unmeasured urinary anions HCO 3 - the major unmeasured urinary cations NH 4 + HCO 3 - excretion in healthy subjects - usually negligible NH 4 + daily average excretion - approximately 40 mEq/L –results in a positive or near-zero gap

43 Acid-Base Metabolic acidosis / Urinary AG Urine AG = ([Na+] + [K+]) - [Cl-] in metabolic acidosis –the kidneys increase the amount of NH 3 synthesized to buffer the excess H+  NH 4 Cl excretion increases the increased unmeasured NH 4 +  increases the measured anion Cl- in the urine,  a negative AG == a normal response to systemic acidification the finding of a positive urine AG in a non-AG metabolic acidosis == a renal acidification defect: renal tubular acidosis [RTA]

44 Acid-Base Metabolic acidosis / Urinary AG Caveats the presence of ketonuria makes this test unreliable the negatively charged ketones are unmeasured  urine AG will be positive or zero despite the fact that renal acidification and NH4 + levels are increased severe volume depletion from extrarenal NaHCO3 loss  avid proximal Na+ reabsorption  little Na+ reaching the lumen of the collecting duct is reabsorbed in exchange for H+ limited H + excretion  reduced NH 4 + excretion  positive urinary AG

45 Acid-Base Metabolic acidosis / Effect of potassium balance on acid-base status transcellular shift of K + –intracellular K + is exchanged for extracellular H + or vice versa  influence on renal acid secretion in hypokalemia  intracellular acidosis in hyperkalemia  intracellular alkalosis

46 Acid-Base Metabolic acidosis / Effect of potassium balance on acid-base status Hypokalemia –increased renal production of NH 3  increase in renal acid excretion _____ __ –relative intracellular acidosis  increased HCO 3 - reabsorption –relative intracellular acidosis  high activity of the apical Na + /H + exchanger The increase in NH 3 production by the kidneys may be significant enough to precipitate hepatic encephalopathy in patients who have advanced liver disease. Correcting the hypokalemia can reverse this process.

47 Acid-Base Metabolic acidosis / Effect of potassium balance on acid-base status increased renal ammoniagenesis  relatively alkaline urine excessive NH 3 then binds more H + in the lumen of the distal nephron  increased urine pH  suggestion of RTA as an etiology for non-AG acidosis –differential diagnoses  urine AG negative in patients with normal NH 4 + excretion positive in patients with RTA

48 Acid-Base Metabolic acidosis / Effect of potassium balance on acid-base status causes for hypokalemia + metabolic acidosis –most common - GI loss: diarrhea, laxative use –less common - renal loss of potassium secondary to RTA or salt-wasting nephropathy differential diagnoses –the urine pH –the urine AG –the urinary K + concentration

49 Acid-Base Metabolic acidosis / Effect of potassium balance on acid-base status Hyperkalemia –opposite effect to hypokalemia –reduction of NH 3 synthesis in the proximal tubule  reduction of NH 4 + reabsorption in the thick ascending limb  reduced medullary interstitial NH 3 concentration  decrease in net renal acid secretion causes for hyperkalemia + metabolic acidosis –primary or secondary hypoaldosteronism treatment for hyperkalemia + metabolic acidosis –hyperkalemia has the central role in the generation of the acidosis  lowering serum the K + concentration  correction of the associated metabolic acidosis

50 Acid-Base Metabolic acidosis / History symptoms - not specific –patients may report varying degrees of dyspnea hyperventilation respiratory center stimulation in an effort to compensate for the acidosis –nausea, vomiting, and decreased appetite clinical history –helpful in establishing the etiology (related to the underlying disorder ) –the age of onset and a family history – to point to inherited disorders

51 Acid-Base Metabolic acidosis / History important points in the history: –diarrhea - GI losses of HCO 3 - –history of diabetes mellitus, alcoholism, or prolonged starvation - accumulation of ketoacids –polyuria, increased thirst, epigastric pain, vomiting - diabetic ketoacidosis (DKA) –nocturia, polyuria, pruritus, and anorexia - Renal failure 4 –ingestion of drugs or toxins - Salicylates, acetazolamide, cyclosporine, ethylene glycol, methanol –visual symptoms - methanol ingestion –renal stones - RTA or chronic diarrhea –tinnitus - salicylate overdose

52 Acid-Base Metabolic acidosis / Physical Kussmaul respirations = the best recognized sign –a form of hyperventilation  increase minute ventilatory volume –slow, deep breathing  an increase in tidal volume rather than respiratory rate stunted growth and rickets  chronic metabolic acidosis in children coma and hypotension  acute severe metabolic acidosis other physical signs  the underlying cause –xerosis, scratch marks on skin, pallor, drowsiness, fetor, asterixis, pericardial rub  renal failure –reduced skin turgor, dry mucous membranes, fruity smell  DKA

53 Acid-Base Metabolic acidosis / Causes Metabolic acidosis –normal AG (ie, non-AG) –high AG Non-AG metabolic acidosis also characterized by hyperchloremia (hyperchloremic acidosis) causes of non-AG metabolic acidosis (mnemonic ACCRUED ) –acid load –chronic renal failure –carbonic anhydrase inhibitors –renal tubular acidosis –ureteroenterostomy –expansion/extra-alimentation –diarrhea

54 Acid-Base Metabolic acidosis / Causes The conditions that may cause a non-AG metabolic acidosis 1.GI loss of HCO Diarrhea, enterocutaneous fistula (eg, pancreatic), enteric diversion of urine (eg, ileal loop bladder), pancreas transplantation with bladder drainage 2.Renal loss of HCO Proximal RTA (type 2), carbonic anhydrase inhibitor 3.Failure of renal H + secretion - Distal RTA (type 1), type 4 RTA, renal failure 4.Acid infusion - Ammonium chloride, hyperalimentation 5.Other - Rapid volume expansion with normal saline, urinary diverting surgical procedures (eg, ureteroenterostomy)

55 Acid-Base Metabolic acidosis / Causes RTA metabolic acidosis occurs from decreased net renal acid secretion

56 Acid-Base Metabolic acidosis / Causes / RTA CharacteristicsProximal (Type 2)Distal (Type 1)Type 4 Primary defectProximal HCO3 - reabsorption Diminished distal H+ secretion Diminished ammoniagenesis Urine pH<5.5 when serum HCO3 - is low >5.5 <5.5 Serum HCO3 ->15 mEq/LCan be <10 mEq/L >15 mEq/L Fractional excretion of HCO3 - (FEHCO3) >15-20% during HCO3 - load <5% (can be as high as 10% in children) <5% Serum K+Normal or mild decrease Mild-to-severe decrease* High Associated featuresFanconi syndrome Diabetes mellitus, renal insufficiency Alkali therapyHigh dosesLow doses ComplicationsOsteomalacia or rickets Nephrocalcinosis, nephrolithiasis

57 Acid-Base Metabolic acidosis / Causes The conditions that may cause a high-AG metabolic acidosis 1.Azotemia 2.Ketoacidosis 3.Lactic acidosis 4.Salicylate overdose 5.Ethylene glycol poisoning 6.Methanol poisoning 7.Paraldehyde poisoning

58 Acid-Base Metabolic acidosis / Causes / high-AG metabolic acidosis mnemonic = SLUMPED 1.salicylate 2.lactate 3.uremia 4.methanol 5.paraldehyde 6.ethylene glycol 7.diabetes

59 Acid-Base Metabolic acidosis / Causes/ high-AG metabolic acidosis to narrow the differential diagnosis of high-AG acidosis - osmolar gap plasma osmolality –can be calculated using the following equation: Posm = [2 X Na+]+[glucose in mg/dL]/18+[BUN in mg/dL]/2.8 –can also be measured in the laboratory other solutes normally contribute minimally to serum osmolality  the difference between the measured and the calculated value (osmolar gap) is no more than mOsm/kg some osmotically active toxins = methanol, ethylene glycol, acetone –cause a high-AG acidosis –increase the osmolar gap measuring the osmolar gap  narrowing the differential diagnosis of high-AG acidosis

60 Acid-Base Metabolic acidosis / Causes / non-AG metabolic acidosis AG = [Na+] - ([Cl-] + [HCO3 -]) for a patient with metabolic acidosis (with a decrease in HCO3 -) to maintain a normal AG, an equal increase in [Cl-] must occur  hyperchloremic metabolic acidosis hyperchloremic metabolic acidosis –HCO3 - lost GI tract the kidneys –renal acidification defect

61 Acid-Base Metabolic acidosis / Causes / non-AG metabolic acidosis non-AG metabolic acidosis mechanisms 1.addition of HCl to body fluids: H+ buffers HCO3 - and the added Cl- results in a normal AG 2.loss of HCO3 - from the kidneys or the GI tract: the kidneys reabsorb sodium chloride to maintain volume 3.rapid volume expansion with normal saline: this results in an increase in the chloride load that exceeds the renal capacity to generate equal amounts of HCO3 -

62 Acid-Base Metabolic acidosis / Causes / non-AG metabolic acidosis Specific causes of hyperchloremic metabolic acidosis Loss of HCO3 - via the GI tract –the secretions of the GI tract, with the exception of the stomach, are relatively alkaline -high concentrations of base (50-70 mEq/L) –significant loss of lower GI secretions  metabolic acidosis, especially when the kidneys are unable to adapt to the loss by increasing net renal acid excretion –such losses - diarrheal states, fistula with drainage from the pancreas or the lower GI tract, vomiting if it occurs as a result of intestinal obstruction, laxatives abuse –treatment - replacing the lost HCO3 – –urine pH < 5.3 a negative urine AG (normal urine acidification) increased NH4 + excretion if distal Na+ delivery is limited because of volume depletion, the urine pH cannot be lowered maximally

63 Acid-Base Metabolic acidosis / Causes / non-AG metabolic acidosis Specific causes of hyperchloremic metabolic acidosis 1.Distal RTA (type 1) a decrease in net H+ secreted by the A-type intercalated cells of the collecting duct H+ is secreted by the apical –H+ –ATPase and –K+/H+ –ATPase(more important in K+ regulation than in H+ secretion) the secreted H+ is excreted –as free ions (urine pH value) –titrated by urinary buffers, phosphate, and NH3 decreased secreted H+ amount –  reduction in its urinary concentration (ie, increase in urine pH) –  reduction in total H+ buffered by urinary phosphate, NH3

64 Acid-Base Metabolic acidosis / Causes / non-AG metabolic acidosis Specific causes of hyperchloremic metabolic acidosis Type 1 RTA should be suspected in any patient with non-AG metabolic acidosis and a urine pH greater than 5.0 patients have a reduction in serum HCO3 - to various degrees, in some cases to less than 10 mEq/L mechanisms implicated in the development of distal RTA –a defect in 1 of the 2 proton pumps, H+ –ATPase or K+ -H+ –ATPase acquired or congenital –a defect in the basolateral Cl-/HCO3 - exchanger, AE1, or the intracellular carbonic anhydrase that can be acquired or congenital –back-diffusion of the H+ from the lumen via the paracellular or transcellular space (lost integrity of the tight junctions)

65 Acid-Base Metabolic acidosis / Causes / non-AG metabolic acidosis Specific causes of hyperchloremic metabolic acidosis Early renal failure metabolic acidosis is usual in patients with renal failure in early to moderate stages of chronic kidney disease (glomerular filtration rate of mL/min), it is associated with a normal AG (hyperchloremic) in more advanced renal failure, the acidosis is associated with a high AG in hyperchloremic acidosis, reduced ammoniagenesis (secondary to loss of functioning renal mass) is the primary defect, leading to an inability of the kidneys to excrete the normal daily acid load NH3 reabsorption and recycling may be impaired, leading to reduced medullary interstitial NH3 concentration In general, patients tend to have a serum HCO3 - level greater than 12 mEq/L, and buffering by the skeleton prevents further decline in serum HCO3 - !!! patients with hypobicarbonatemia from renal failure cannot compensate for additional HCO3 - loss from an extrarenal source (eg, diarrhea) and severe metabolic acidosis can develop rapidly

66 Acid-Base Metabolic acidosis / Causes / high-AG metabolic acidosis Specific causes of metabolic acidosis Lactic acidosis –L-lactate = a product of pyruvic acid metabolism in a reaction catalyzed by lactate dehydrogenase that also involves the conversion of nicotinamide adenine dinucleotide (NADH) to the oxidized form of nicotinamide adenine dinucleotide (NAD+). This is an equilibrium reaction that is bidirectional, and the amount of lactate produced is related to the reactant concentration in the cytosol (pyruvate, NADH/NAD+) –daily lactate production in a healthy person is substantial (approximately 20 mEq/kg/d), and this is usually metabolized to pyruvate in the liver, the kidneys, and, to a lesser degree, in the heart. Thus, production and use of lactate (ie, Cori cycle) is constant, keeping plasma lactate low –the major metabolic pathway for pyruvate is to acetyl coenzyme A, which then enters the citric acid cycle –in the presence of mitochondrial dysfunction, pyruvate accumulates in the cytosol and more lactate is produced

67 Acid-Base Metabolic acidosis / Causes / high-AG metabolic acidosis Specific causes of metabolic acidosis Lactic acidosis lactic acid accumulates in blood whenever production is increased or use is decreased a value greater than 4-5 mEq/L is considered diagnostic of lactic acidosis –type A lactic acidosis occurs in hypoxic states –type B occurs without associated tissue hypoxia –D-lactic acidosis is a form of lactic acidosis that occurs from overproduction of D- lactate by intestinal bacteria- it is observed in association with intestinal bacterial overgrowth syndromes

68 Echilibrul acidobazic

69 Acid-Base Metabolic acidosis / Causes / high-AG metabolic acidosis Specific causes of metabolic acidosis Ketoacidosis –free fatty acids released from adipose tissue have 2 principal fates. In the major pathway, triglycerides are synthesized in the cytosol of the liver –in the less common pathway, fatty acids enter mitochondria and are metabolized to ketoacids (acetoacetic acid and beta-hydroxybutyric acid) by the beta-oxidation pathway –ketoacidosis occurs when delivery of free fatty acids to the liver or preferential conversion of fatty acids to ketoacids is increased –this pathway is favored when insulin is absent (as in the fasting state), in certain forms of diabetes, and when glucagon action is enhanced

70 Acid-Base Metabolic acidosis / Causes / high-AG metabolic acidosis Specific causes of metabolic acidosis Ketoacidosis –alcoholic ketoacidosis occurs when excess alcohol intake is accompanied by poor nutrition –alcohol inhibits gluconeogenesis, and the fasting state leads to low insulin and high glucagon levels –these patients tend to have a mild degree of lactic acidosis –this diagnosis should be suspected in alcoholic patients who have an unexplained AG acidosis, and detection of beta-hydroxybutyric acid in the serum in the absence of hyperglycemia is highly suggestive –patients may have more than one metabolic disturbance (eg, mild lactic acidosis, metabolic alkalosis secondary to vomiting)

71 Acid-Base Metabolic acidosis / Causes / high-AG metabolic acidosis Specific causes of metabolic acidosis Ketoacidosis –starvation ketoacidosis can occur after prolonged fasting and may be exacerbated by exercise –type 1 diabetes by stressful conditions (eg, infection, surgery, emotional trauma), but it can also occur in patients with type 2 diabetes. hyperglycemia, metabolic acidosis, and elevated beta-hydroxybutyrate confirm the diagnosis. the metabolic acidosis in DKA is commonly a high-AG acidosis secondary to the presence of ketones in the blood after initiation of treatment with insulin, ketone production ceases, the liver uses ketones, and the acidosis becomes a non-AG type that resolves in a few days (ie, time necessary for kidneys to regenerate HCO3 -, which was consumed during the acidosis

72 Horacio J. Andorgué & Nicolaos E. Midias

73 Echilibrul acidobazic

74 Acid-Base Metabolic acidosis / Causes / high-AG metabolic acidosis Specific causes of metabolic acidosis Advanced renal failure –patients with advanced chronic kidney disease (glomerular filtration rate of less than 20 mL/min) –present with a high-AG acidosis –the acidosis occurs from reduced ammoniagenesis leading to a decrease in the amount of H+ buffered in the urine –the increase in AG is thought to occur because of the accumulation of sulfates, urates and phosphates from a reduction in glomerular filtration and from diminished tubular function –in persons with chronic uremic acidosis, bone salts contribute to buffering, and the serum HCO3 - level usually remains greater than 12 mEq/L –this bone buffering can lead to significant loss of bone calcium with resulting osteopenia and osteomalacia


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