Integrative Physiology
Volume disorders
Circulation disorders
Kidney disorders
Electrolyte disorders
Osmolarity disorders Acid-Base disorders
Respiratory disorders
O2/CO2 transport disorders
Gastrointestinal disorders
Acid-Base disorders
Homeostasis of internal enviroment
Disorders of the acid-base chemistry, influence of
respiration, lungs and altered metabolism
Outputs
Inputs
Storage
Balance between input and output flow
depletion
retention?
?
extracellular fluid - ECF
intracellular fluid - ICF
Metabolism
ConcentrationsBalance estimation
External environment of organism
plasma
interstitial fluid - ISF
intracellular fluid - ICF
Metabolism
Concentrations
extracellular fluid -ECF
capillaries
Lymph
External environment of organism
Balance estimation
intravascular
fluid
intracellular fluid - ICF
Metabolism
plasma blood cells
(part of ICF)
extracellular fluid -ECF
capillaries capillaries
Lymph
External environment of organism
interstitial fluid - ISF
intravascular
fluid
intracellular fluid - ICF
Metabolism
plasma
capillaries
transcellular fluid
extracellular fluid -ECFcapillaries
Lymph
External environment of organism
blood cells
(part of ICF)
interstitial fluid - ISF
intravascular
fluid
intracellular fluid - ICF
Metabolism
plasma
capillaries
Lymph
extracellular fluid -ECF
LungsGIT
Kidney
„exc
hang
ers“
blood cells
(part of ICF)
interstitial fluid - ISF transcellular fluid
External environment of organism
intravascular
fluid
intracellular fluid - ICF
Metabolism
plasma
capillaries
Lymph
extracellular fluid -ECF
LungsGIT
Kidney
„exc
hang
ers“
Circulation„mixing“
blood cells
(part of ICF)
interstitial fluid - ISF transcellular fluid
External environment of organism
intravascular
fluid
intracellular fluid - ICF
Metabolism
plasma
capillaries
Lymph
extracellular fluid -ECF
LungsGIT
Kidney
„exc
hang
ers“
Circulation„mixing“
blood cells
(part of ICF)
interstitial fluid - ISF transcellular fluid
External environment of organism
intravascular
fluid
intracellular fluid - ICF
Metabolism
plasma
capillaries
Lymph
extracellular fluid -ECF
LungsGIT
Kidney
„exc
hang
ers“
Circulation„mixing“
blood cells
(part of ICF)
interstitial fluid - ISF transcellular fluid
External environment of organism
CO2 H +
ACID-BASE BALANCE
CO2
H2O
H2CO3
HCO3
-
H+
A-
TA+NH4
+
20 000 mmol/24 hod 60 mmol/24 hod
60 mmol/24 hH+ excretion
Practically complete reabsorbtion of HCO3-
Metabolic production od strong acidsMetabolic production of CO2
Acid-Base Balance
Buffering systems of the blood
H2CO
3
HCO3-H+CO2
HBufBuf-
Hb- HHb
Alb-
HAlb
HPO42- H2PO4
-
H2O
H+
H+
H+
H+
++
+
+
+
+
non-bicarbonate buffersBuf = Hb + Alb + PO4
-
Buffering reactions
H2CO
3
HCO3-
H+
CO2
HBuf
Buf-
H2O
Acid-Base Balance
Acid Balance Base Balance
Diet -> 2H++SO42-
Diet ->H+ + HPO4-
Diet -> 3K++ 3 HCO3-
2H++2HCO3- -> 2CO2+2H2O Glucose -> 3H++Citrate-
2NH4++SO4
-
H2PO42-
3K++Citrate-
Production of H+
Removal of H+
Add „new“ HCO3-
Removal of HCO3-
Production of HCO3-
Excrete organic anions
Urine
H+ formation/removalGlucose -> Lactate- + H+
C16 fatty acids -> 4 ketoacids anions- + 4 H+
Cysteine -> urea + CO2+H2O+SO42- + 2 H+
Lysine+ -> urea + CO2 + H+
Lactate- + H+ -> GlucoseGlutamate- + H+ -> urea + CO2+H2O
Citrate- + 3 H+ -> CO2+H2O
Glucose -> Glycogen or + CO2+H2O
Triglyceride -> CO2+H2O
Alanine -> urea + glucose or CO2+H2O
Reactions that yields H+ (more negative charge in products than in substrates)
Reactions that removes H+ (more net positive charge in products than in substrates)
H+ are neither produced nor removed (neutrals to neutrals)
Diet
Sulfur-AA
SO42-
2 H+
2 HCO3-
2CO2+2H2O
Glutamine
2NH4+
2NH4+
SO42-
urine
kidney
ECF
Diet
RNA-P-
HPO42-
H+
HCO3-
CO2+H2O
CO2+H2O
H+HPO4-
urine
kidney
ECF
Diet
K+
H+
urinekidney
ECFOA-
CO2+H2O
HCO3-
OA utilisationGlucose
OA- H+
CO2+H2O
liver
OA-
K+
OA-
CO2
H2O
H2CO3
HCO3
H+
Buf -
HBuf
-
TA + NH4+
CO2 balance
H+ balance1. Buffer systems (msec)2. Respiration control (12 hours)3. Kidney control (3-5 days)
Acid-base regulation
Exchange H+/K+ H+/Na+ between cells and ECFRole of liver in AB regulation
CO2
H2O
H2CO3
HCO3
H+
Buf -
HBuf
-
TA + NH4+
CO2 balance
H+ balance
Buffer system acid-base disturbances
Balance acid-base disturbances:
- respiration acidosis/alkalosis
- metabolic acidosis/alkalosis
Acid-base disturbances:
CO2
H2O
H2CO3
HCO3
H+
Buf -
HBuf
-
TA + NH4+
Buffers system acid-base disturbances:Dilutional acidemiaContractional alkalemiaHypoproteinemic alkalemia
CO2 balance
H+ balance
CO2
H2O
H2CO3
HCO3
H+
Buf -
HBuf
-
TA + NH4+
Buffers system acid-base disturbances:Dilutional acidemia
Dilution
CO2 balance
H+ balance
CO2
H2O
H2CO3
HCO3
H+
Buf -
HBuf
-
TA + NH4+
equilibrium shift
CO2 balance
H+ balance
Buffers system acid-base disturbances:Dilutional acidemia
Dilution
CO2
H2O
H2CO3
HCO3
H+
Buf -
HBuf
-
TA + NH4+
Hemoconcentration
CO2 balance
H+ balance
Buffers system acid-base disturbances:Contractional alkalemia
CO2
H2O
H2CO3
HCO3
H+
Buf -
HBuf
-
TA + NH4+
CO2 balance
H+ balance
Hemoconcentration
Buffers system acid-base disturbances:Contractional alkalemia
CO2
H2O
H2CO3
HCO3
H+
Buf -
HBuf
-
TA + NH4+
equilibrium shift
CO2 balance
H+ balance
Hemoconcentration
Buffers system acid-base disturbances:Contractional alkalemia
CO2
H2O
H2CO3
HCO3
H+
Buf -
HBuf
-
TA + NH4+
Acute hypoproteinemia
CO2 balance
H+ balance
Buffers system acid-base disturbances: Hypoproteinemic alkalemia
CO2
H2O
H2CO3
HCO3
H+
Buf -
HBuf
-
TA + NH4+
Acute hypoproteinemia
equilibrium shift CO2 balance
H+ balance
Buffers system acid-base disturbances: Hypoproteinemic alkalemia
CO2
H2O
H2CO3
HCO3
H+
Buf -
HBuf
-
TA + NH4+
CO2 balance
H+ balance
Buffer system acid-base disturbances
Balance acid-base disturbances:
- respiration acidosis/alkalosis
- metabolic acidosis/alkalosis
Acid-base disturbances:
-25 -20 -15 -10 -5 0 5 10 15 20 25 30
10
20
30
40
50
60
70
80
90PCO2 torr
Base Excess mmol/l
pH=7
,1
pH=7
,2
pH=7
,3
pH=7,37
pH=7,43
pH=7,5
pH=7,6
Acute metabolic acidosis Akute metabolic alkalosis
Acut
e re
spira
tory
aci
dosi
Acute respiratory acidosis
Sustained metabolic alkalosis
Sustained metabolic acidosis
Sustained re
spira
tory alkalosis
Sust
aine
d re
spira
tory
acid
osis
CO2
H2O
H2CO3
HCO3
-
Buf -
HBuf
H+
A-
H+ retentionH+ depletion
TA+NH4+
Bicarbonate reabsorbtion
(3) losses of
HCO3
-
(4) diarhoeaH+excretion
(1) Increased metabolic production of strong acids
(2) Disorder of H+ excretion
Na+
Cl-
HCO3-
Na+
Cl-
HCO3-
Na+
Cl-
Anion gap
HCO3-
Accumulation of anions of strong acids(laktate acidosis
ketoacidosisuremic acidosis)
A- HCO3-
Cl-
H+
NH4+Cl-
NH3
H+
NH4+
NH3Cl-Relative accumulation of chlorides
Decreased acidification(tubular acidosis, hypoaldosteronisms, decreases glomer. filtration)
Normal aniongap
Increasedanion gap
Gastrointestinal losses of bicarbonate
HCO3-
Cl-
Na+
K+ Cl-
Na+
K+
Cl-
In urine:[K+]+[Na+]-[Cl-] < 0
in urine:[K+]+[Na+]-[Cl-] >= 0
Overdosis of NH4Cl
H+
Urea
HCO3-
HCO3-
Metabolic acidosis with:-increased anion gap-normal anion gap
Diarrhoea
H2O H2O
H2O
Na+
Cl-
H20 + CO2
Colon
HCO3-
HCO3-
Cl-
Cl-
AE
HCO3-
HCO3-
H20 + CO2
Na+
Na+
H+
H+
NHE
Cl-
Na+
H2O
Cl-
H2O
H2O
H2O
Alkalic diarrhoea
Hypertonic dehydratation
Hyperchloremic acidosis
Na+
ColonAE
HCO3-
HCO3-
Cl-
Cl- HCO3-
H20 + CO2
HCO3-
HCO3-
Hypotonic fluid lossHCO3
-
H20 + CO2
NHE
Na+H+
H+
Na+
Cl-
NHE AE
Cl-
Na+
H2O
Na+
Na+
H+
H+
HCO3-
HCO3-
Cl-
H20 + CO2
Cl-
H2O
H2O
HCO3-
HCO3-
HCO3-
H2O
Severe alkalic diarrhoea
Hypotonic fluid loss
Hypertonic dehydratation
Hyperchloremic acidosis
K+
Potassium loss
Na+
Cl-
Colon
HCO3-
H20 + CO2
Cl-
Na+
H2O
Cl-
H2O
H2O
H2O
Hypertonic dehydratation
Hypochloremic alkalosis
Na+
Colon
Histidine
HCO3-
Hypotonic fluid lossHCO3
-
H20 + CO2
H.Histidine+Cl-
NHE
Na+H+
H+
Na+
HCO3-
HCO3-
Cl-
Cl- HCO3-
H20 + CO2
AE
Acidic diarrhoea in DRA, down-regulated adenoma
10 15 20 25
Rate
of b
icar
bona
te re
abso
rbtio
n
Plasma level of HCO3-
Complete reabsorbtion
norm
proximal tubular renal acidosis
norm
normpH=5,5
Decreased acidification(tubular acidosis, hypoaldosteronisms, decreases glomer. filtration)
Cl-
H+
NH4+
NH3Cl-
HCO3-
Cl-
Na+
K+
Cl-
HCO3-
HCO3-
Positive urine aniongap
In urine:[K+]+[Na+]-[Cl-] > 0
Cl-
Normal urine aniongap
Na+
K+Cl-
In urine:[K+]+[Na+]-[Cl-] < 0
H+HCO3
-
Cl- NH4+
NH4+
Normal acidification
a
pH=7,8
a
b
pH=6,5
b
c
c
pH=5,5
Na+
Cl-
HCO3-
Anion gap
Na+
HCO3-
normalanion gap
Cl-
Hyperchloremic acidosis with normal anion gap
CO2
H2O
H2CO3
HCO3
-
Buf -
HBuf
H+
A-
Retence H+
Retence H
TA+NH4+
Bicarbonate reabsorbtion
(6) vomiting
H+excretion
(7) K+
depletion
hyperaldosteronism
katabolism
K+
H+
Overdosis HCO3- infusion
Metabolic alkalosis
-25 -20 -15 -10 -5 0 5 10 15 20 25 30
10
20
30
40
50
60
70
80
90PCO2 torr
Base Excess mmol/l
pH=7
,1
pH=7
,2
pH=7
,3
pH=7,37
pH=7,43
pH=7,5
pH=7,6
Acute metabolic acidosis Akute metabolic alkalosis
Acut
e re
spira
tory
aci
dosi
Acute respiratory acidosis
Sustained metabolic alkalosis
Sustained metabolic acidosis
Sustained re
spira
tory alkalosis
Sust
aine
d re
spira
tory
acid
osis
Vomiting
CO2 H2O
H2CO3
HCO3-
H+
Cl-
Cl-
Stomach
Duodenum and pancreas
CO2 H2O
H2CO3
H+ +HCO3- H+
Cl-
H2CO3
CO2
H2O
Balanced
CO2
hypochloremia
CO2 H2O
H2CO3
HCO3-
H+
Cl-
Cl-
Stomach
Duodenum and pancreas
CO2 H2O
H2CO3
H++HCO3- H+
Cl-
H2CO3
CO2
H2O
Unbalanced, HCO3- retension
Cl-
H+
Hypotonic fluid loss
Hypertonic dehydratation
Hypochloremic alkalosis
CO2
H+
Cl-
H+
K+
K+
H+
K+
H+
Paradoxal urine acidification
Potassium depletion
Increases lossse ofn
Intracellular fluid
Primary cause: Losses of Cl- a H+ by
vomiting
Metabolic alkalosis
H+
Cl-
K+
K+
H+
Na+
Glomerulal filtration (hypochloremic
alkalosis)
Increased exchange Na+ with K+ and Na+ with H+
Excretion of potassium increases,acidification of urine regardless of alkalosis
Na+
Glomerular filtraton (norm)
Readsorbtion of sodium and chlorides
Depletion of chlorides
Cl-
Cl-
Na+
Na+
Remnant of sodium is exchanged with and H+
K+
K+
H+
H+
NH4+
Na+/Cl- reabsorbtion is diminished
Cl-
Na+
Na+
-25 -20 -15 -10 -5 0 5 10 15 20 25 30
10
20
30
40
50
60
70
80
90PCO2 torr
Base Excess mmol/l
pH=7
,1
pH=7
,2
pH=7
,3
pH=7,37
pH=7,43
pH=7,5
pH=7,6
Acute metabolic acidosis Akute metabolic alkalosis
Acut
e re
spira
tory
aci
dosi
Acute respiratory acidosis
Sustained metabolic alkalosis
Sustained metabolic acidosis
Sustained re
spira
tory alkalosis
Sust
aine
d re
spira
tory
acid
osis
-25 -20 -15 -10 -5 0 5 10 15 20 25 30
10
20
30
40
50
60
70
80
90PCO2 torr
Base Excess mmol/l
pH=7
,1
pH=7
,2
pH=7
,3
pH=7,37
pH=7,43
pH=7,5
pH=7,6
Acute metabolic acidosis Akute metabolic alkalosis
Acut
e re
spira
tory
aci
dosi
Acute respiratory acidosis
Sustained metabolic alkalosis
Sustained metabolic acidosis
Sustained re
spira
tory alkalosis
Sust
aine
d re
spira
tory
acid
osis
PO2
Concentration of O2
PaO2PvO2
Arterial blood at pH=7,4
Venose blood at pH=7,2
Oxygen released due to shift
of dissotiacion curve(Bohr effect)
Oxygen released due drop
PO2
PO2
Concentration of O2
High PaO2 during hyperventilation
at respiratory alkalosis
PvO2
Arterial blood at pH=7,4(normal conditions)
Venous blood at pH=7,2(normal conditions)
normal PaO2
Venous blood at pH=7,36(alkalemia)
Arterial blood at pH=7,6
(alkalemia)
Release of oxygen at normal condition
Release of oxygen at respiratory alkalosis
Decrease of oxygen delivery
to tissues at acute
respiratory alkalosis
-25 -20 -15 -10 -5 0 5 10 15 20 25 30
10
20
30
40
50
60
70
80
90PCO2 torr
Base Excess mmol/l
pH=7
,1
pH=7
,2
pH=7
,3
pH=7,37
pH=7,43
pH=7,5
pH=7,6
Acute metabolic acidosis Akute metabolic alkalosis
Acut
e re
spira
tory
aci
dosi
Acute respiratory acidosis
Sustained metabolic alkalosis
Sustained metabolic acidosis
Sustained re
spira
tory alkalosis
Sust
aine
d re
spira
tory
acid
osis
Mixed acid-base disturbances - examples
Metabolic acidosis + respiratory acidosis
Metabolic acidosis + respiratory alkalosis
Diarrhoea -> metabolic acidosis + vomiting -> metabolic alkalosis+ catabolism, ->lactate metabolic acidosis
Potassium, Acid-Base and volume
1
K+mmol/l
6,9
2
3
4
5
6
7
8
7,0 7,1 7,2 7,3 7,4 7,5 7,6 7,7 7,8 pH
Normal kalemia rangeA
K+
H+ H+
K+
A: Norm
B
K+
H+ H+
K+
B: Acidemia - exchange K+ / H+
K+
C
K+
H+ H+
K+
C: long lasting acidemia - K+ depletion
K+
D
K+
H+ H+
K+
D: Rapid alkalinization - H+/K+ - dangerous hypokalemia
K+
Potassium depletionFrom 10% to 50%
Normal or increased intake of potassium
from 5% to 30%
K+
Intracellular acidosis in proximal tubule
Enhanced resorption HCO3
-
K+
H+
H+
Enhanced resorption Cl-
Enhanced resorption Cl-
Effect of hypokalemia on
ECF volume
K+K+
Diuretics (Furosemid)
Large delivery of sodium in CCD (e.g. in osmotic diuresis) Low chloride in CCS
Hypealdosteronism
Potassium depletion
Catabolism
Long lasting acidemia
K+K+
Oliguric phase of acute renal failure
Hypoaldosteronism(m. Addisoni)
Potassium retention
Tubular damage(e.g. interstitial nephritis, diabetic nephropathy)
ACID-BASE BALANCE
Danish School of acid-base balance
"Modern" approach to acid-base balance by Stewart and Fencl
?
Classical approach of "Danish School"
Problem:
How to measure PCO2?
Measurement of Acid-Base parameterspH, pCO2, [HCO3
-]
HCO3-
H+
Buf-
HBuf
CO2
H2O
H2CO3
pH, pCO2, [HCO3-]
HCO3-
H+
Buf-
HBuf
CO2
H2O
H2CO3
Measurement of Acid-Base parameters
pH, pCO2, [HCO3-]
HCO3-
H+
Buf-
HBuf
CO2
H2O
H2CO3
Alkaline reserve
Measurement of Acid-Base parameters
pH, pCO2, [HCO3-]
HCO3-
H+
Buf-
HBuf
CO2
H2O
H2CO3
Measurement of Acid-Base parametersP. Astrup 1956
Equilibration method for pCO2 measurement by Astruplog PCO
2
pH
Titration curve
pH In blood sample (before equilibrationí
pH after equilibration with low pCO2
Low level pCO2 In mixture
O2/CO2
pH after equilibrationwith high pCO2
High level pCO2 in mixture
O2/CO2
pCO2 in measered sample
CO2
H2O
H2CO3
HCO3
H+
Buf -
HBuf
-
Buffer Base (BB)
BB = [HCO3
- ]+ [Buf
- ]
depends on cHb
Normal buffer base:NBB=41.7+0.42*cHB [g/100ml]
Base Excess:BE=BB-NBB
CO2
H2O
H2CO3
HCO3
H+
Buf -
HBuf
-
+ 1 mmol H+ added to 1 litre of blood
CO2
H2O
H2CO3
HCO3
H+
Buf -
HBuf
-
1 mmol/l drop of [HCO3-] + [Buf-]
BE=-1mmol/l
+ 1 mmol H+ added to 1 litre of blood
CO2
H2O
H2CO3
HCO3
H+
Buf -
HBuf
-
+ 1 mmol OH- added to 1 litre of blood
CO2
H2O
H2CO3
HCO3
H+
Buf -
HBuf
-
1 mmol/l increase of [HCO3-] + [Buf-]
BE= 1mmol/l
+ 1 mmol OH- added to 1 litre of blood
log pCO2
pH
Plasma and blood with different hematocrit
BE=0
7.4
40 torr BE=-5
BE=-10
BE=5
BEcurve
reading of BE
Odečet BB
NBB=41,7 + 0,42 * cHB
Buffer reactions
H2CO
3
HCO3-H+CO2
HBufBuf-
Hb- HHb
Alb-
HAlb
HPO42- H2PO4
-
H2O
H+
H+
H+
H+
++
+
+
+
+
Buffer reactions
H2CO
3
HCO3-H+CO2
HBufBuf-
Hb- HHb
Alb-
HAlb
HPO42- H2PO4
-
H2O
H+
H+
H+
H+
++
+
+
+
+
Nebikarbonátové pufryBuf = Hb + Alb + PO4
-
H2CO
3
HCO3-
H+
CO2
HBuf
Buf-
H2O
Buffer reactions
HCO3-
H+
Buf-
HBuf
CO2
H2O
H2CO3
BB=[HCO3-] +[Buf-] = const
Siggaard-Andersen
Siggaard-Andersen
BE=0 mEq/l
BE=-15 mEq/l
Siggaard-Andersen (1960-1962)
Definition only for standard conditions not included hypo/hyperalbuminemia hyper/hypophosphatemia SA nomogram initialy was defined at 38°C
Definition (for blood in vitro)
- Buffer Base: [BB]=[HCO3-]+[Buf-] (independent on pCO2)
-Normal Buffer Base: [NBB][BB] při pH=7.4 při pCO=40 torr at givenHb(SA nomogram - at normal albumins, phophates)
-Base Excess: [BE]=[BB]-[NBB]
Siggaard-Andersen (1974-1995)
Definition (for blood in vitro)
- Buffer Base: [BB]=[HCO3-]+[Buf-] (independent on pCO2)
-Normal Buffer Base: [NBB][BB] při pH=7.4 při pCO=40 torr at givenHb(SA nomogram - at normal albumins, phophates)
-Base Excess: [BE]=[BB]-[NBB]
Definition NBB dependent on Hb, albumin and phosphates
Problems of Danish school
• Problems: In patients with acute disturbances of nonbikarbonate buffers :
e.g. altered plasma concentrations
( if the original SA nomogram is used)
Stewart theory (1983)
Ca+ Mg+
HCO3-
Buf-
XA-
Cl-
Na+
K+
SID[H+] [OH-] = K'w[Buf-]+[HBuf] = [BufTOT]
[Buf-] [H+] = KBuf [HBuf]
[H+] [HCO3-] = M × pCO2
[H+] [CO32-] = N × [HCO3
-]
SID+ [H+]– [HCO3-] – [Buf-]– [CO3
2-]– [OH-] = 0
Peter Stewart
Stewart theory – solution of equations
[H+]4 + (SID + KBUF) [H+]3 +
+(KBUF (SID - [BufTOT])- K'w-M×pCO2)[H+]2
- (KBUF(K'w2 + M × pCO2)-N×M×pCO2)[H+]
- K'w×N×M×pCO2 = 0
pH = f (pCO2, SID, BufTOT)
Mathematical wizardry
dependency of variables = causality
pH = f (pCO2, SID, BufTOT)
Vladimír Fencl
H2O/Na+/Cl-/K+ balance
CO2 balance
Plasma protein balance
pCO2
SID
[BufTot]
pH
[HCO3-]
H2O/Na+/Cl-/K+ balance
CO2 balance
Plasma protein balance
pCO2
SID
[BufTot]
pH
[HCO3-]
Stewart‘s „modern approach
LungsVentilationPerfusion
TissuesPerfusionMetabolismTransport
CO2
STRONG IONS
CO2
KIDNEYSFiltrationResorptionSecretion
STRONG IONS
GITAbsorbtionSecretion
STRONG IONS
KREV
Independent variables
PCO2
SID
[BufTOT]
Dependent variables
[HCO3-]
[Buf-]
[CO32-]
[OH-]
[H+] (pH)
LIVERSynthesisDegradation
PROTEINS
BALANCE THEORYExcretion of CO2 in
the lungs
The excretion of strong acids in the kidney
Metabolic production of strong acids
CO2 production
Blood Volume
Extracellular fluid volume Arterial Pressure
return
Starling curve and venous return curve
Strenous excercise
Rest
Decompensated cardiac failure
Treatment od decompensated cardiac failure
High-output cardiac failure
return