1. Metabolic processes producing and
consuming H+.
Buffer systems in the body.
Acid-base balance in the body and its
control.
2011 (E.T.)
1
2. The production and regulation of hydrogen ions
in the body Acids are continuously produced
Liquids, food in the body and threaten the
normal pH of the body fluids
ICT Metabolic processes
CO2 H+
OH-
ECT CO2 + H2O ⇔ H2CO3 ⇔ HCO3- + H+ ⇔ bufferY
Lung Kidneys
CO2 HCO3- NH4+, H2PO4-, SO42-
2
~ 20 mol /d 1 mmol/d 40-80 mmol/d
3. Sources of acids in metabolism :
1/ volatile carbonic acid:
● the source is CO2 - from decarboxylations
● CO2 with water gives weak volatile carbonic acid
● the exchange of CO2 ( 15 – 25 mol . d-1 ) between the blood
and the external environment secure the lungs
2/ nonvolatile acids:
● sulfuric acid - from sulfur-containing amino acids (Cys + Met)
● phosphoric acid - from phosphorus-containing compounds
● carboxylic acids (e.g. lactate, acetoacetate, 3-hydroxybutyrate),
unless they are completely oxidized to CO2
and water
● nonvolatile acids cannot be removed through the lungs,
they are excreted by the kidney into the urine
( 40 – 80 mmol . d-1 ) 3
4. The limit value of pH (blood)
Although there is a large
production of acidic
metabolites in the body, pH = 7,40
concentrations of H+
ions in biological fluids
[H+] ≅ 40 nmol . l-1
are maintained in the The human body is
very more tolerant of
narrow range: acidaemia (acidosis)
than of alkalaemia
(alkalosis).
pH = 6,80 pH = 7,70
[H ] ≅ 160 nmol . l
+ -1 [H+] ≅ 20 nmol . l-1
4
Steep decrease or increase of pH may be life-threatening
6. Buffer systems in blood
Hydrogen carbonate buffer - the most important buffer in blood
CO2 + H2O H2CO3 H+ + HCO3–
− −
[HCO3 ] [HCO3 ]
pH = pK (H 2CO3 ) + log = 6,1 + log
[CO 2 + H 2 CO 3 ] [ H 2CO3 ] ef
Effective concentration of carbonic acid [CO2 + H2CO3] = 0,23 x pCO2
0,23 is the coefficient of solubility of
CO2 for pCO2 in kPa
Physiological values:
pCO2 5,3 kPa ± 0,5 kPa. HCO3- 24 ± 2 mmol/l
In these equations, the concentrations [HCO3-] and [CO2+H2CO3] are expressed in 6
mmol/l, not in the basal SI unit mol/l !
9. The other buffer systems in organism
The protein buffers – mainly albumin
H-proteinn− H+ + protein(n+1)− (based on dissociation of histidine
In blood ∼ 7%, important intracellulary
Hemoglobin buffer
O2 pKA ~ 7,8 O2
HHb Hb− + H+
pKA ~ 6,2
HHbO2 HbO2− + H+
Phosphate buffer
pKA2 = 6,8
H2PO4− HPO42− + H+
It contributes to intracellular buffering, important for buffering of 9
urine. In plasma only ∼5%.
10. Transport of O2 and CO2 between the tissues and lungs
– cooperation of hydrogencarbonate and hemoglobine
Blood in lungs Blood in tissues
Erc Erc
O2 O2 O2 O2 O2 O2
HHb HHb
HbO2− HCO3 −
HCO3− HbO2−
H+ H+
HCO3− HCO3−
Cl− Cl-
H2CO3 H2CO3
CA CA
H2O H2O
CO2 CO2 CO2 CO2
CO2 CO2
Chloride shift in venous blood
10
11. Tissues
pCO2 in arterial blood ∼5,3 kPa
CO2 difunding from cells increases pCO2 up to ∼6,3 kPa
The amount of CO2 dissolved in plasma increases, CO2 difuses into ercs
HCO3- is formed in red blood cells by the action of carboanhydrase, it partially binds to
Hb (carbaminohemoglobin)
H+ ions are buffered by Hb in ercs
Concentration of HCO3- in ercs is higher than in plasma, HCO3- diffuses out of the red
cells, Cl- diffuses into the red cell to maintain electroneutrality. (Hamburgers shift)
Lung
pCO2 in alveols is lower than in venous blood, CO2 diffuses into alveols.
HCO3- in red blood cells binds H+, that is released at reoxygenation of Hb and CO2 is
formed.
Concentration of HCO3- in ercs decreases, exchange of bicarbonate for chloride in red
blood cells flushes the bicarbonate from the blood and increases the rate of gas exchange
11
12. Forms of CO2 transport in blood
Form of CO2 Occurence in
plasma (%)
HCO3− ~ 85
Carbamino proteins ~ 10
Physically dissolved ~5
12
13. The respiratory system regulates acid base
balance by controlling the rate of CO2 removal
Peripheral chemoreceptors in arterial walls and central
chemoreceptors in brain
Increase of [H+] in arterias at metabolic disturbances, or ↑of pCO2
in CNS activates medullary respiratory center that stimulates
increased ventilation promoting elimination of CO2
Conversely, the peripheral chemoreceptors reflexely suppres
respiratory activity in response to a fall in arterial H+ concentration
resulting from non-respiratory causes.
13
14. Kidneys function in maintaning acid-base balance
Tubular cell Tubular lumen
HCO3− HPO42−
Activation at
Na+ A−
alkalemia
H+ H+ HCO3−
Gln
+ acidosis NH4+
NH4 +
Glu
Na+ H2CO3
+ acidosis
2-OG ATP
H+
H2O CO2 CO2 H2O A−
carboanhydrase
H2CO3
Cl-
Na+ HPO42−
HCO3−
H+ H+
Na+ Competition
with K+ H2PO4−
14
~30 mmol/day
15. Kidneys control the pH of body fluids by
adjusting three interrelated factors
• H+ excretion
• HCO3- excretion
• ammonia secretion from tubular cells
15
16. Tub.cell lumen
H secretion in proximal tubulus
+
ATP
H+
H+
H+-ATPase
Na+
Antiport with Na+
H+ secretion in distal tubulus and collecting duct
Type A intercalated cells:
Active secretion of H+ into urine – H+ -ATPase, H+-K+ -ATPase
HCO3- resorption
Type B intercalated cells:
HCO3- secretion
H+ 16
17. Kidneys and HCO3- Reabsorption of HCO3-
occurs in proximal
tubulus and A type
Reabsorption of HCO3- intercalated cells
HCO3-
CO2 Secretion of H+ from three
H2O H +
sources:
OH- • CO2 from plasma
H2CO3
ca • CO2 from tubular fluid
HCO 3
-
CO2 CO2 ca •CO2 produced within the
CO2 H2O tubular cell
OH -
H2O H+
ca – carboanhydrase 17
18. Kidney and NH3
Production of NH3 from
glutamate and glutamin in
tubular cells is increased at
acidosis.
NH3 difuses into the tubular
gln ATP
H + fluid and buffers H+ ions
NH4 that are secreted from
glu NH3 tubular cells
NH3
2-oxoglu NH4
H+
Na+
18
19. Urinary buffers
H+ transporters in tubular cells and collecting duct can secrete H+
against the concentration gradient until the tubular fluid becomes 800
times more acidic than plasma. At this point, further secretion stops,
because the gradient becomes too great for the secretory process to
continue. The corresponding pH value is 4,5.
Tub.cell lumen
H+ ions are buffered by:
HPO4-
ATP
HPO4 (filtered from blood)
-
H+
H2PO4-
NH3 secreted from tubular cells H+
Na+
NH3 NH4
If more buffer base is available in the urine, more H+ can be secreted 19
20. Summary of renal responses to acidosis and alkalosis
abnormality H+ H+ HCO3- HCO3- pH of Change of pH
secretion excretion resorption excretion urine in plasma
Acidosis ↑ ↑ ↑ - acidic Alkalinization
to normal
Alkalosis ↓ ↓ ↓ ↑ alkaline Acidification
to normal
Kidneys requires hours to days to compensate for changes in body fluid pH
(compared to the immediate responses of the body buffers and the few minute
delay before the respiratory systém responds)
However, kidneys are the most potent acid-base regulatory system
20
21. Contribution of liver to maintenance of acid base
balance
2-OG Kidneys URINE
Liver
acidemia + Gln Gln NH4+ NH4+
+
NH3 2NH4+ H+
acidemie
AK urea
CO2 + H2O H2CO3 H+ + HCO3− urea
Two ways of NH3 elimination in the liver
urea synthesis (connected with release of 2H+ - acidifying process)
glutamin synthesis (without release of H+)
Higher synthesis of glutamin is stimulated at acidosis, synthesis of urea is
21
potentiated at alkalosis.
22. Main indicators of acid-base state
Measured parameters
pH 7,40 ± 0,04
pCO2 5,3 ± 0,5 kPa
(pO2, Hb, HbO2, COHb, MetHb)
Measuring by means of acid-base analyzers
22
23. Derived (calculated) parameters
Actual HCO3− concentration 24 ± 3 mmol/l
is the concentration of bicarbonate (hydrogen carbonate) in the plasma of
the sample. It is calculated using the measured pH and pCO2 values.
Base excess (BE, base excess) 0 ± 3 mmol/l
is the concentration of titratable base when the blood is titrated with a
strong base or acid to a plasma pH of 7.40 at a pCO2 of 5.3 kPa and 37
°C at the actual oxygen saturation.
It is calculated for plasma, blood or extracelular fluid.
Arterial oxygen saturation (sO2) 0,94–0,99
is defined as the ratio between the concentrations of O2Hb and HHb +
O2Hb
Information about contration of the main electrolytes (Na+, K+, Cl−, Pi) and 23
albumin are also important
24. Dependent and independent variables of acid base
balance
• Dependent variables: pH, BE a HCO3-
These variable are not subject to independent alteration. Their
concentrations are governed by concentrations of other ions and
molecules.
• Independent variables: pCO2, SID, weak
nonvolatile acids Atot
the concentration of each of the dependent variables is uniquely and
independently determined by these three independent variables
(primary changes in concentrations of some cations (mainly
Na+) and anions (Cl−, albumin, phosfphate and unmeasured
ions) triggers consequently the changes of acid-base 24
parameters).
25. The complementary calculations are derived from
principle of plasma electroneutrality
[Na+] + [K+] + [Ca2+] + [Mg2+] = ([Cl-] + [HCO3-] + [albx-] + [Piy-] + [UA-])
UA- - unmeasured anions (see later)
25
26. Some complementary calculations
Anion gap 150
AG = [Na+] + [K+] − ([Cl−] + [HCO3−]) Na+
Cl-
Cl-
16 ± 2 mmol/l 100
HCO3-
Higher value of AG indicates the presence of extra
K+
unmeasured anions e.g. lactate, acetoacetate, 3- 50
Albx-
hydroxybutyrate.
Ca2+ AG
Piy-
The value is often corrected on serum albumin Mg2+
UA-
concentration:
*AGkorig=AG + 0.25 x ([Alb]norm- [Alb]zjišt
* Information about empirical formulas are given only for ilustration, students need
not to know them 26
27. Some complementary calculations
Albumin charge Albx-
It is calcultaed from albumin concentration (g/l) and pH
11,2 mmol/l at pH =7,4 a [alb]= 40 g/l
Phosphate charge Piy-
It is calculated from pH and concentration of phosphates
1,8 mmol/l at pH =7,4 a [Pi]=1 mmol/l
Corrected chloride ion concentration
correcting the chloride concentration for changes in Na+
[Cl]kor = [Cl]zjišt.x [Nanorm.] / [Nazjišt]
27
28. Some complementary calculations
Unmeasured anions
[UA] = ([Na+] + [K+] + [Ca2+] + [Mg2+]) – ([Cl−] + [HCO3−] +[Albx-] +[Piy-] )
6-10 mmol/l
UA expresses the concentration of other 150
anions that are not included in the
equation of electroneutrality (e.g.lactate, Na+
Cl-
Cl-
keton bodie, glycolate at poisonning with
ethylene glycol, formiate at poisonning 100
with methanol, salicylates etc.)
Increased value of UA is compensated by HCO3-
K +
decrease of concetration of other anions
or mainly HCO3- 50
Albx-
Ca2+
Piy-
Mg2+ 28
UA-
29. Some complementary calculations
SID (strong ion difference)
SIDeff = [Na+] + [K+] + [Ca2+] + [Mg2+] – ([Cl-] + [UA-])
38–40 mmol/l
150
Accurate measurement of SID is
complicated by difficulties with Cl-
Cl-
Na +
determination of UA (unmeasured
100
anions), empirical relation is therefore
used
HCO3-
SIDeff = [HCO3−] + 0,28∙[albumin] + 1,8∙[Pi] K+
[Pi] and [HCO3-] are in mmol/l and albumin in SID
50
g/l Albx-
Ca2+
Piy-
Mg2+
UA- 29
30. Classification of acid-base disorders
„acidosis“ (pH < 7,36) metabolic disorder
[HCO3-]
pH = pK H CO + log
2 3
[CO2 + H2CO3 ]
„alkalosis“ (pH > 7,44) respiratory disorder
30
Disturbances are often combined.
31. Classification of acid-base disorders according to the
primary cause
Respiratory disorder
the primary change in pCO2 due to low pulmonary ventilation
or a disproportion between ventilation and perfusion of the lung.
Metabolic disorder
the primary change in buffer base concentration (not only
HCO3–, but also due to changes in protein, phosphate, and
strong ions concentrations).
Quite pure (isolated) forms of respiratory or metabolic disorders don't exist in
fact, because of rapid initiation of compensatory mechanisms; however, full
stabilization of the disorder may settle in the course of hours or days.
31
32. −
HCO3 20
pH = 6,1 + log = 6,1 + log = 7,4
pCO2 .0,22 1
Change of Change of the ratio Change of Typ acute
parameter HCO3-/pCO2 pH disturbance
pCO2 ↑ Resp.acidosis
↓ ↓
HCO3 -
-
concentration
pCO2 ↓ Resp.
↑ ↑ alkalosis
Change of HCO3 -
-
concentration
pCO2 - Metab.
↓ ↓ acidosis
HCO3- ↓
concentration
pCO2 - Metab.
↑ ↑ alkalosis
HCO3- ↑
concentration 32
33. The classification of A-B disorders according
to time manifestation
acute (uncompensated)
stabilized (compensated)
- simple metabolic disorders or simple respiratory disorders
practically do not exist, because the compensation processes
begin nearly immediately, however the stabilization can also
take some days (in dependence on the type of disorder)
33
34. Compensatory processes
Compensation
The secondary, physiological process occurring in response to
a primary disturbance in one component of acid/base
equilibrium whereby
the component not primarily affected changes in such a
direction as to restore blood pH towards normal.
Metabolic disorders of acid-base balance are modified by
respiratory compensation and oppositely
Correction
The secondary, physiological process occurring in response to
a primary disturbance whereby the component that is
primarily affected is restored to normal. 34
.
35. Time course of regulatory responses
Buffer systems Organ
ECT ICT bone lung liver kidney
Full immed min/hours h/days Development of hours/days days
efectivity iately compenzation
The primary respiratory disorder leads to a compensatory change in HCO3–
reabsorption by the kidney, which reaches its maximal effectivity in 5 – 7 days.
In the primary metabolic disorder, a change in blood pH evokes a rapid change
in the pulmonary ventilation rate (during 2 – 12 hours).
35
36. Acid-base balance graph
→ overall evaluation (pH, pCO2 a BE) of acid base balance
7,1 7,2 7,3 7,37 7,43 pH
12,0
7,5
10,6 uRAc
9,8 aRAc
7,6
8,0 uMAlk
6,7
pCO2 normal
5,3 aMAlk
(kPa) aMAc values
4,0
uMAc
2,7
1,3
uRAlk aRAlk
-20 -10 0 10 20 30
BE (mmol/l)
36
Ac acidosis, Alk alkalosis; M metabolic, R respiratory; a accute, u stabilized
37. Example of acid-base balance disturbance
Metabolic acidosis (MAc)
Causes of MAc
• Increased production of H+ - lactacidosis
- ketoacidosis (starvation, non-compensated DM)
- acidosis from retention of non volatile acids in renal failure
2. Exogenous gain of H+ - metabolites at intoxication with methanol, ethylen glycol,
- overdosing with acetylsalicylic acid
- NH4Cl infusion at the treatment of MAlk
3. Loss of HCO3- - diarhea, burns, renal disturbances
4. Relative dilution of plasma – excessive infusion of isotonic solutions
37
38. Correction and compensation of MAc
↑H+
1. Effect of buffers : H+ + HCO3- → H2CO3 → H2O + CO2
−
HCO3- ↓ HCO3 20
< pH <7.4
pCO2 .0,22 1
2. respiratory compensation – increase of pulmonary ventilation
−
HCO3 20
pCO2 ↓ ≈
pCO2 .0,22 1
pH approches to 7,4, but concentrations of HCO3- and pCO2 are non physiological
3. Renal correction (development during 2–3 days) - acidic urine is excreted.
Excretion of H+ is accompanied by excretion of the given anion (A−) (lactate,
acetacetate, 3-hydroxybutyrate). HCO3− consumed during buffering reaction is
38
regenerated in renal tubuli.
39. Grafical description of changes during
compensation and correction of MAc
7,1 7,2 7,3 7,37 7,43 pH
12,0
7,5
10,6 uRAc
9,8 aRAc
7,6
8,0 uMAlk
6,7
pCO2 normal
(kPa)
5,3
aMAc 1 aMAlk
3 values
4,0
uMAc 2
2,7
1,3
uRAlk aRAlk
-20 -10 0 10 20 30
BE (mmol/l)
39
40. Changes of electrolyte parameters during acid-base
disturbances (example)
Acidosis
The cause: loss of HCO3-
(e.g.diarrhea)
Na + Cl
Cl-
-
Loss of HCO3- is replaced
by Cl- → hyperchloremic
acidosis HCO3-
K+ SID ↓
50
Albx-
Ca2+
Piy-
Mg2+
UA-
40
UA not changed AG not changed
41. Acidosis
cause – production of lactate, keton bodies, formiate,
salicylate etc.
Due to buffering reaction 150
concentration of [HCO3-],
event. Albx- a Piy- is decreased Na + Cl
Cl-
-
Concentration of
unmeasured anions (UA)
increases HCO3-
Concentration of chlorides
K+ SID ↓
50
is not changed –
Albx-
normochloremic acidosis Ca2+
Piy-
Mg2+
UA-
UA ↑
AG ↑ 41
42. Dilution acidosis – consequence of plasma dilution
By the dilution the 150
concentration of
buffer bases falls Cl
Cl-
-
Na +
HCO3-
K+ SID ↓
50
Albx-
Ca2+
Piy-
Mg2+
UA-
AG ↓ 42
UA ↓
45. Evaluation of acid –base parameters (1)
1/ pH, pCO2, BE – type of disturbance, measure of compensation
pH= 7,367, pCO2 = 5,25 kPa, BE = - 2,5 mmol.l-1
45
46. Evaluation of acid –base parameters (2)
2/ recalculation of laboratory results
• calculation of [Albx-] and [Piy-]
• calculation of unmeasured anions [UA-]
• correction of Cl- to actual content of water
46
47. Evaluation of acid –base parameters (2)
the deviations of patient values from the reference values are
filed to the columns „acidosis“ / „alkalosis“
(according to their signs: „+“ for increase, „−“ for decrease)
mmol . l-1 patient acidosis alkalosis
[Na+] 140 − +
[Cl-]correc 100 + −
[UA-]correc 8 + −
[Pi-] 2 + −
[Alb-] 12 + −
47
