1. dia

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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
a pCO2
Respiratory component
Altered by respiratory compensation for metabolic
disorders
Primarily altered in respiratory disorders
The result of the interplay between metabolic and
respiratory components
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Extracellular pH
7.4
7.1
6.9
6.7
240
6.7
200
160
Cellular (H) nmol/l
Cellular pH
120
6.9
7.1
80
7.4
40
7.7
0
80
40
120
200
(H) nmol/l
Buffering of Strong Acid added to
Extracellular Fluid
Compartment Contribution
Time course
40 50 10 PCO2 HCO-3
Instantaneous Rapid Slow Min Hrs/days
Extracellular fluid Cells Bone and connective
tissue
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
Buffering
EC
IC
Bone
Compensation
Lung
hyperventillation
pCO2 1,0 1,5 (HCO-3)
(CO2 34-31 mmHg 18mmol HCO-3)
Kidney
total acid excretion
UNH4 V UTA V U HCO-3V
1mmol/kg/day max. ca. 600 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 12-20
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 HCO3
other anions )
Increased acid formation -diabetic
ketoacidosis -alcoholic lactic acidosis
Toxic materials -salycilate
-methanol -ethylen
glycol
Acid excretion -ARF, CRF
AG (HCO-3 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
Buffering by ECF and intracellular buffers
Bone buffering
? Nephron population
? Solute and water load per nephron
? Filtered phosphate
? 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. 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 -pregn
ancy
Intoxication -Ethanol -Etlylenglycol
-Strychnine Muscular hyperactivity
-seizures -marathon running
Cardiogenic shock Hypovolemic shock Septic
shock Hypoxemia (O2 lt 35mmHg) Anemia
ATP
NADH
Venous constriction Arteriolar dilatation Myocordi
al contraction
Congrestive Heart failure (pH7.10-7.20)
lactate
mortality
If gt 4 mmol /l
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Lactic Acidosis
Increased lactic acid production
Decreased lactate metabolism
? anion gap
? H ? lactate
? HCO3-
? Distal nephron delivery of lactate (if plasma
lactate gt 7 to 8 mmol/l)
? pH
? Distal nephron anion (lactate) delivery
? Na lacate- excretion
? Renal NH3 production
? ECF volume
Buffering (ECF ICF)
? Difference in lumen negative potential
? Ventilation
? Distal nephron Na avidity
? Renal H secretion
? Renal TA excretion
? Renal NH4 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 - Lupus erythematosus
Primary Cystinosis Wilsons 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-3 hypercloremic metabolic
alkalosis
urine Na , K , H2O
Hyponatremia, hypokalemia, hypovolemia
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NORMAL
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HCO-3 Reabsorption (meq/L GFR)
COMPLETE REABSORPTION
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PROXIMAL ( Type II) RTA
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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 5.5 pH 6.5 pH 7.8
Bicarbonate titration curve and segmental
nephron deliver and absorption in proximal (type
II) RTA
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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
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PROXIMAL TUBULE CELL
Na
CAIII
ATP
ADP
HCO3-
Pi
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-de
pendent Rate-dependent Hypoaldosteronism
Amphotericin B Classic distal
RTA Amiloride, obstructive nephropathy,
sickle cell disease Interstitial
nephropathy Hyporeninemic 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
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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
Netto H loss (vomiting hyperaldosteronism)
Netto HCO-3 increase (milk-alkali syndrome,
baking powder)
Cl- lossgtHCO-3 loss (diureticum)
Buffering ( ICEC) HCO3 H CO2H2O
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
?pCO20.25-1.0 ? HCO-3 (Fe pCO2 43-50 mmHg
34mmol/l (HCO-3)
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Metabolic alkalosis
NASOGASTRIC SUCTION
REMOVAL OF
WATER
POTASSIUM
HYDROGEN ION
SODIUM
CHLORIDE
? PLASMA HCO3-
?pH
?PLASMA AND FILTERED Cl-
?ECF VOLUME
H SHIFTS INTO ECF K SHIFTS INTO CELLS
? ALDOSTERONE
? FILTERED HCO3-
HYPOVENTILATION ? PaCO2
HYPOKALEMIA
K EXCRETION
? HCO3- REABSORPTION
MAINTENANCE OF METABOLIC ALKALOSIS
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Differential Diagnosis of Metabolic Alkalosis
Sodium chloride-responsive (UCl- lt10 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- lt 20 mmoles/L)
Excess mineralocorticoid activity Hyperaldosteron
ism Cushings syndrome Bartters
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-con
trolled ventilation Inadequate frequency, tidal
volume settings Large dead space Total
parenteral nutrition (increased CO2
production)
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Acute Respiratory Acidosis
? pCO2 ? pH ? pO2 ? act. HCO3 st. HCO3 ?
?HCO3- (?pCO2/10)?3
(f.e. HCO3- 24-30 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 Pick
wickian syndrome Poliomyelitis Diaphragmatic
paralysis Thoracic-pulmonary disorders Chronic
obstructive airway disease Kyphoscoliosis End-st
age interstitial pulmonary disease
Laboratory
? pCO2 ? pH ? pO2 ? act. HCO3 ? st. HCO3-
?HCO3 4x ?pCO2/10 ?4
(f.e. HCO3 32-40 mmol/l ? pCO2 70 mmHg)
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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 Pe
ripheral stimulation of respiration Pulmonary
emboli Congestive heart failure Interstitial
lung diseases Pneumonia Stiff lungs without
hypoxemia Altitude Uncertain Hepatic
insufficiency Gram-negative septicemia Mechanica
l or voluntary hyperventilation
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Respiratory Alkalosis
Acute
?HCO3 - 1-3x (?pCO2/10)
(f.e. HCO3 - 23-21 mmHg ? pCO2 30 mmHg)
Chronic
?HCO3 - 2-5x (?pCO2/10)
(f.e. HCO3 - 22-19 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- 23-21
mmol/l)
Chronic respiratory alkalosis ?HCO3- 2-5x
(?pCO2/10) (f.e. pCO2 30 mmHg ? HCO3- 22-19
mmol/l)
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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)
Hyperventilation Respiratory alkalosis 7.46
20 14 34
Vomiting Metabolic alkalosis 7.53 44 36
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Hypovolemic shock Metabolic acidosis 7.35
30 16 32