integrative physiology

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

StorageBalance between input and output flow

depletion

retention?

?

extracellular fluid - ECF

intracellular fluid - ICF

Metabolism

ConcentrationsBalance estimation

External environment of organism

plasma

interstitial fluid - ISF


Metabolism

Concentrations

extracellular fluid -ECF

capillaries

Lymph


Balance estimation

intravascular

fluid


Metabolism

plasma blood cells(part of ICF)


capillaries capillaries

Lymph



intravascular

fluid


Metabolism

plasma

capillaries

transcellular fluid

extracellular fluid -ECFcapillaries

Lymph


blood cells(part of ICF)


intravascular

fluid


Metabolism

plasma

capillaries

Lymph


LungsGIT

Kidney

„exc

hang

ers“


interstitial fluid - ISF transcellular fluid


intravascular

fluid


Metabolism

plasma

capillaries

Lymph


LungsGIT

Kidney

„exc

hang

ers“

Circulation„mixing“




intravascular

fluid


Metabolism

plasma

capillaries

Lymph


LungsGIT

Kidney

„exc

hang

ers“

Circulation„mixing“




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

H2CO3

HCO3-H+CO2

HBufBuf-

Hb- HHbAlb-

HAlbHPO4

2- H2PO4-

H2O

H+

H+

H+

H+

++

+

+

++

non-bicarbonate buffersBuf = Hb + Alb + PO4

-

Buffering reactions

H2CO3

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+

urine kidney

ECFOA-

CO2+H2O

HCO3-

OA utilisation Glucose

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


CO2

H2O

H2CO3

HCO3

H+

Buf -

HBuf

-

TA + NH4+

equilibrium shift

CO2 balance

H+ balance

Hemoconcentration


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

spiratory alkalosis

Susta

ined

resp

irato

ry ac

idos

is

CO2

H2O

H2CO3

HCO3-

Buf -

HBuf

H+

A-

H+ retentionH+ depletion

TA+NH4+

Bicarbonate reabsorbtion

(3) losses of

HCO3-

(4) diarhoea H+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


Hyperchloremic acidosis

K+

Potassium loss

Na+

Cl-

Colon

HCO3-

H20 + CO2

Cl-

Na+

H2O

Cl-

H2O

H2O

H2O


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


Acut

e re

spira

tory

aci

dosi




Sustained re

spiratory alkalosis

Susta

ined

resp

irato

ry ac

idos

is

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


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


Acut

e re

spira

tory

aci

dosi




Sustained re

spiratory alkalosis

Susta

ined

resp

irato

ry ac

idos

is

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


Acut

e re

spira

tory

aci

dosi




Sustained re

spiratory alkalosis

Susta

ined

resp

irato

ry ac

idos

is

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

H2CO3

HCO3-H+CO2

HBufBuf-

Hb- HHbAlb-

HAlbHPO4

2- H2PO4-

H2O

H+

H+

H+

H+

++

+

+

++

Buffer reactions

H2CO3

HCO3-H+CO2

HBufBuf-

Hb- HHbAlb-

HAlbHPO4

2- H2PO4-

H2O

H+

H+

H+

H+

++

+

+

++

Nebikarbonátové pufryBuf = Hb + Alb + PO4

-

H2CO3

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 approachLungsVentilationPerfusion

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

integrative physiology

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