Patholphysiology of Acid base Balance Altered by respiratory compensation for metabolic disorders...
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Patholphysiology of Acid base Balance
Altered by respiratory compensation for metabolic disorders
Primarily altered in metabolic disorders
Altered by buffering
Altered by renal compensation for respiratory disorders
pH = pKa+ + log
[ HCO3- ]
α pCO2
Metabolic component
Respiratory component
Primarily altered in respiratory disorders
The result of the interplay between metabolic and respiratory components
1H+
3 000 000 Na+EC:
Buffering of Strong Acid added to Extracellular Fluid
Compartment Contribution Time course
Physochemical buffering
Extracellular fluid
Cells
Bone and connective tissue
Physiological regulation
40%
50%
10%
PCO2
HCO-
3
Instantaneous
Rapid
Slow
Min
Hrs/days
Extracellular pH
40
80
120
160
200
240
Cel
lula
r (H
+)
nmol
/l
7.77.4
7.1
6.9
6.7
Cel
lula
r pH
0 40 120 200
(H+) nmol/l
7.4 7.1 6.9 6.7
80
Respiratory
Renal
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
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
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-3*V
1mmol/kg/day max. ca. 600 mmol/kg/day
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
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
AG : (HCO-3 Cl- - reabsorption hypercloremia):
Gastrointertinal loss: Renal loss -diarrhea etc. - Carbonic anhydrase inhibitors - pancreatic fistula - Renal tubular acidosis (RTA)
- Hyperparathyroidism - Hyperaldosteronism
Acid excretion
-ARF, CRF
~ Ø
Failure of Acid Excretion in Renal Disease
Bone buffering
Daily acid load
Buffering by ECF and
intracellular buffers
Diseased kidney
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
Urinary HCO3
- leak
Complete HCO3
- reabsorption
Acid urine
NH4 excretion
Titratable acid
excretion relative to degree of acidosis
Net acid excretion
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.
Causes of Lactic Acidosis
Clinically characterised by decrease in tissue oxigenation
Cardiogenic shock
Hypovolemic shock
Septic shock
Hypoxemia (O2 < 35mmHg)
Anemia
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
ATP NADH
lactate
mortality
If > 4 mmol /l
Venous constriction
Arteriolar dilatation
Myocordial
contraction
Congrestive
Heart failure
(pH7.10-7.20)
Increased lactic acid production
Generation of HCO3
-
Lactic Acidosis
Decreased lactate metabolism
anion gap H+ + lactate
HCO3-
Renal NH3 production
Distal nephron anion (lactate)
delivery ECF volume
Difference in lumen negative potential
Buffering (ECF + ICF)
pH
Ventilation
Distal nephron delivery of lactate(if plasma lactate > 7 to 8 mmol/l)
Na+ lacate- excretion
Distal nephron Na+ avidity
Renal H+ secretion
Renal TA excretion
Renal NH4+
excretion
Generation of HCO3
-
pCO2
Rise in pH toward normal
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
PrimaryCystinosisWilson’s diseaseLead toxicityCadmium toxicityMercury toxicityAmyloidosisMultiple myelomaNephrotic syndromeEarly renal transplant injuryMedullary cystic diseaseOutdated tetracycline
Causes of Renal Tubular Acidosis
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
HC
O- 3 R
eabs
orpt
ion
(meq
/L
GF
R)
15
20
25
COMPLETE REABSORPTION
NORMAL
PROXIMAL ( Type II) RTA
15 20 25
TR
ESH
OL
D
Plasma
(HCO-3) (meq/L)
Filtered load
Proximal reabsorption
Distal delivery
Distal reabsorption
Urinary excretion
pH 5.5 pH 6.5 pH 7.8
60%
15%
Norm:
„6” „8” „10”
~ 80%: ~ 20
15%: ~ 4-6
„4 ~ 6”
Bicarbonate titration curve and segmental nephron deliver and absorption in proximal (type II) RTA
Proximal RTA (type II): hypokalemic, hyperchloremic metabolic acidosis (in acidosis: net acid excretion = acid generated)
2
8
6
K+
Na+
HCO3- H2CO3 CO2
HCO3-
H2O
CAIV
H+
CO2
OH-
CAIII
3
41
5
ADP
7 Pi
ATPADPPi
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).
LUMEN
PROXIMAL TUBULE CELL
BLOOD
Defect Mechanism Example
Gradient or backleak
Secretory
Voltage-dependent
Rate-dependent
Hypoaldosteronism
Amphotericin B
Classic distal RTA
Amiloride, obstructive nephropathy, sickle cell disease
Interstitial nephropathy
Hyporeninemic hypoaldosteronism
Pathophysiologic Mechanisms of Distal Renal Tubular Acidosis
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
Classical Distal RTA (type I): hypokalemic, hyperchloremic metabolic acidosis (in urine: inappropriate acidification)
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.
H2PO4- (TA)
LUMEN
H+
1
HPO4
NH3 NH4+
3
ATP Pi
ADP
H2ODISTAL TUBULE
BLOOD
OH-
CO2CA
HCO
3-
2
Cl-
Metabolic alkalosis
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
ΔpCO2=0.25-1.0 * Δ HCO-3
(Fe: pCO2 43-50 mmHg 34mmol/l (HCO-3)
Kidney: HCO3- secretion
Maintaining factors:
1. Hypocloremia prox. tub. HCO-
3 – reabs.
2. Hypokalemia „paradox aciduria”
3. Hypovolemia
4. Hyperaldosteronism
WATER POTASSIUM
NASOGASTRIC SUCTION
REMOVAL OF
HYDROGEN ION
PLASMA HCO3- pH
SODIUM CHLORIDE
ECF VOLUME
PLASMA AND FILTERED Cl-
H+ SHIFTSINTO ECFK+ SHIFTSINTO CELLS
HYPOKALEMIA
FILTERED HCO3- HYPOVENTILATION
PaCO2
ALDOSTERONE
K+ EXCRETION
HCO3- ” REABSORPTION”
MAINTENANCE OF METABOLIC ALKALOSIS
Metabolic alkalosis
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)
NaCl resistant metabolic alkalosis(f.e.: glycocorticoid therapy)
ECV
H+, K+ excretion HCO3
- reabsorption
Diastalis Na+ reabsorption
NaCl Proximalis NaCl reabsorption
Alkalosis
Differential Diagnosis of Metabolic Alkalosis
Sodium chloride-responsive (UCl- <10 mmoles/L)
Gastrointestinal disordersVomitingGastric drainageVillous adenoma of the colonChloride diarrhea
Diuretic therapy Correction of chronic hypercapnia Cystic fibrosisSodium chloride-resistant (UCl
- < 20 mmoles/L) Excess mineralocorticoid activity
HyperaldosteronismCushing’s syndromeBartter’s syndromeExcessive licorice intake
Profound potassium depletionUnclassified 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
Causes of Acute Respiratory Acidosis
Neuromuscular abnormalitiesBrain stem injuryHigh cord injuryGuillain-Barré syndromeMyasthenia gravisBotulismNarcotic, sedative, or tranquilizer overdose
Airway obstructionForeign bodyAspiration of vomitusLaryngeal edemaSevere bronchospasm
Thoracic-pulmonary disordersFlail chestPneumothoraxSevere pneumoniaSmoke inhalationSevere pulmonary edema
Vascular diseaseMassive pulmonary embolism
Respirator-controlled ventilationInadequate frequency, tidal volume settingsLarge dead spaceTotal parenteral nutrition (increased CO2 production)
pCO2 ; pH ; pO2 ; act. HCO3 ; st. HCO3
[HCO3-] = (pCO2/10)3
(f.e.: [HCO3-] 24-30 mmol/l pCO2 70 mmHg (12-24 ))
Acute Respiratory Acidosis
Causes of Chronic Respiratory Acidosis
Neuromuscular abnormalitiesChronic narcotic or sedative ingestion Primary hypoventilationPickwickian syndromePoliomyelitisDiaphragmatic paralysis
Thoracic-pulmonary disordersChronic obstructive airway diseaseKyphoscoliosisEnd-stage interstitial pulmonary disease
pCO2 ; pH ; pO2 ; act. HCO3 ; st. HCO3-
[HCO3] = 4x pCO2/10 4
(f.e.: [HCO3] 32-40 mmol/l pCO2 70 mmHg)
Laboratory
H2CO3 AND pH
Respiratory acidosis
EFFECTIVE ALVEOLAR VENTILATION
CO2 EXCRETION
PaCO2
RENAL H+ SECRETION
NH4 EXCRETION BALANCED BYCl- EXCRETION
INTRACELLULAR BUFFERS CONSUME H+
NET ACID EXCRETION
HCO3 –
RECLAMATION AND GENERATION
PLASMA HCO
CONCENTRATION
APPROPRIATELY DEFENDED CHRONIC
RESPIRATORY ACIDOSIS
Figure: Schematic time course of the changes in plasma acid-base equilibrium during the development of respiratory acidosis.
Causes of Respiratory Alkalosis
Central stimulation of respirationAnxietyHead traumaBrain tumors or vascular accidentsSalicylatesFeverPainPregnancy
Peripheral stimulation of respirationPulmonary emboliCongestive heart failureInterstitial lung diseasesPneumonia„Stiff lungs” without hypoxemiaAltitude
UncertainHepatic insufficiencyGram-negative septicemia
Mechanical or voluntary hyperventilation
(f.e.: [HCO3 -] 23-21 mmHg pCO2 30 mmHg)
Acute:
[HCO3 -] = 1-3x (pCO2/10)
Chronic:
[HCO3 -] = 2-5x (pCO2/10)
(f.e.: [HCO3 -] 22-19 mmHg pCO2 30 mmHg)
Respiratory Alkalosis
ECF pH
HCO3 RECLAMATION
Acute respiratory alkalosis
[HCO3-]= 1-3x (pCO2/10)
(f.e.: pCO2: 30 mmHg [HCO3-]: 23-21 mmol/l)
Respiratory alkalosis
ALVEOLAR VENTILATION
CO2 EXCRETION
PaCO2
RENAL H+ SECRETION
NH4 EXCRETION TA EXCRETION
INTRACELLULAR BUFFERS ADD H+ TO ECF
BICARBONATURIA
NET ACID EXCRETION
Na+ K+ EXCRETION
PLASMA HCO3 -
CONCENTRATION Chronic respiratory alkalosis
[HCO3-]= 2-5x (pCO2/10)
(f.e.: pCO2: 30 mmHg [HCO3-]: 22-19 mmol/l)
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
Metabolic acidosis and respiratory alkalosis
PaCO2 too low and [HCO3
-] too low for simple disorders
Normal or slightly or
PaCO2 too high and [HCO3
-] too high for simple disorders
Metabolic alkalosis and respiratory alkalosis
Normal or slightly or
Clinical event
Acid-base disorder
pH
PaCO2 (mm Hg)
[HCO3-] (mmoles/l)
Anion gap (mEq/L)
Vomiting
Metabolicalkalosis
7.53
44
36
14
Example of a Triple Acid-Base Disorder
Hypovolemicshock
Metabolicacidosis
7.35
30
16
32
Hyperventilation
Respiratoryalkalosis
7.46
20
14
34