Integrated pathophysiology of fluid,
osmolality, electrolyte and pH
homeostasis (ABB) – part 1
Summary of basic facts - water balance in human body
Volume – osmolality relationship and its changes
Regulation of ABB
Overview of disease impairing V-O matching
Pathophysiology of clinically important disorders
affecting V-O as well as ABB
BODY FLUIDS AND THEIR
COMPOSITION
Body fluid compartments
− water is special and excellent!
• very high specific heat (boils and freezes at
extremes)
• capillary action
− helping many processes (vessels, breastfeeding,
lacrimation, …)
• perfect solvent
• participates in redox reactions (give rise to
ROS)
− processes gaining and loosing water
Hb
circulating blood cells contain ICF
infants 75% water (= risk of dehydration higher –
less solids, they cannot ask for drink)
transcellular fluid in body
cavities typically ignored
(synovia, ocular, CSF, pleura,
pericardium, peritoneum, …)
back up when you bleed (but not too quickly!!!)
Membrane defines the compartments - transport
O2, CO2, urea,
water (osmosis)
through
membrane
(slow) or
aquaporins
(fast)
ligand (cAMP,
hormone) vs.
voltage gated
structural specificity,
competition, saturation
many types of ATP-ases
(Na-K every cell, H+in
kidney, Ca++ in muscle,
K+-H+ stomach proton
pump]
Electrolyte balance ICT/ECT – why like that?
− activity of Na/K ATPase
− selective permeability of K+
− proteins kept inside
• majority of body protein is
intracellular
− Cl- follows the Na+
− phosphate has a gradient
(consumed) inside since
necessary for
• production of ATP
• phosphorylation by kinases
• making Glu-6-P
− clinical example: refeeding syndrome
(e.g. in anorexia nervosa patients)
− hydrogencarbonate establishes
the alkaline reserve
• because the metabolism (happening
inside the cell) produces lots of
acids (that will eventually leave
cell), plasma retains „alkaline
reserve“ to buffer
PO43-HCO3
-
The law of electroneutrality
− in any electrolyte solution the sum of positive
charges equals to the sum of negative ones
− Right: mEq/L = mmol/L for monovalent ions
(e.g. Na and K) but mEq/L must be divided by 2
to convert mmol/L for divalent ions (e.g. Ca and
Mg)
• figures for ECF refer specifically to blood plasma;
interstitial fluid very similar except it has lower
protein and higher chloride concentration.
Osmosis, osmolality & osmotic pressure
− osmosis – a type of passive membrane
transport
• movement of water from its high concentration
(= low concentration of solutes) to low
concentration (= high concentration of solutes)
− osmolality it is about number of molecules
(not size or mass)
• 1mol Glu  1 osmol
• 1mol Cl2  2 osmoles (Cl- + Cl-)
− osmotic pressure
− measured vs. calculated osmolality
• measured by osmometer
• calculated 2xNa+ + Glu/20 + BUN/3 = 290
mOsm/L
− only Na and glucose represent effective osmolality
 BUN freely diffuses across the membrane
− normal interstitium = plasma = ICF
− the difference between m and c = osmolar gap
 normally 10
 if >10 then other molecules present (methanol,
ethanol, ethylene glycol (all 3 causing HAGMA),
sorbitol, mannitol, drugs, …)
more
practical
more
accurate
Osmolality vs. tonicity (made simple)
− osmolality = the total
number of osmoles in given
volume of water
− tonicity = only considers
effective osmoles (cannot
cross the plasma membrane)
in a volume of water
• describes osmotic pressure
gradient
• describes osmolality of the
solution relative to plasma
− isotonic 290 [275 - 295]
− hypotonic <275
− hypertonic >295
− hypertonicity stimulates the
thirst and ADH release
ADH/arginine-vasopressin
Volume – osmolality diagram
Why is this important? for infusion of solutions (crystalloids) to patients
− 60% of TBW
• 40% ICF
• 20% ECF
− 5% plasma
− 15% ISF
 1:3 ratio!!!
− effect of adding
different solutions to
ECF
How to approach volume-osmolality balance problems?
− does the situation affects?
• (1) ECF volume change?
• (2) ECF osmolality change?
− no
− yes (3) ICF volume and osmolality
 water will move by osmosis and the
two compartments will gradually
equilibrate
BODY FLUIDS AND THEIR
COMPOSITION
Acids vs. Bases
− definition: Bronsted-Lowry (1923)
− normal A:B ratio  1:20
• strength is defined in terms of the tendency to donate (or accept) the hydrogen
ion to (from) the solvent (i.e. water in biological systems)
Acid: H+ donor
Base: H+ acceptor
Henderson-Hasselbach equation:
pH = 6.1 + log([HCO3
-] / 0.03 pCO2)
pH
− amount of H+ in the blood is routinely expressed as a pH rather than
absolute concentration in mmol/l because this is ~ million-times lower
than for common electrolytes (e.g. Na+, K+, Ca++, …)
• pH is thus an indirect measure of [H+]
− pH 7 = 110-7 (= 0.0000001) mmol/l
 CAVE! Hydrogen ions (i.e. protons) do not exist free in solution but are linked to
adjacent water molecules by hydrogen bonds (H3O+)
• [H+] by a factor of 2 causes a  pH of 0.3
− neutral vs. normal plasma pH
• pH 7.4 (7.36-7.44)  normal
• pH 7.0  neutral but fatal!!!
pH = -log [H+]
pH 7.40  40 nM
pH 7.00  100 nM
pH 7.36  44 nM
pH 7.44  36 nM
Why is pH so important ?
− [H+] ~ nmol/l, [K+, Na+, Cl-, HCO3
-] ~ mmol/l; however, [H+] is
crucial:
• pH affects function of proteins
 hydrogen bonds = 3-D structure = function
• All the known low molecular weight and water soluble biosynthetic
intermediates possess groups that are almost completely ionised at neutral pH’
 pH-dependent ionisation (i.e. charge) serves to an efficient intracellular trapping of ionised
compounds within the cell and its organelles
− Exceptions:
• macromolecules (proteins)
− mostly charged anyway or size-trapping or hydrophobic
• lipids
− those needed intarcellularly are protein-bound
• waste products
− excretion is desirable
The most important pH for the body is the intracellular pH
− Intracellular pH is maintained at about the pH of neutrality (6.8 at
37˚C) because this is the pH at which metabolite intermediates are
all charged and trapped inside the cell
− Extracellular pH is higher by 0.5 to 0.6 pH units and this represents
about a 4-fold gradient favouring the exit of hydrogen ion from the
cell
 to maintain it at a stable value because of the powerful effects of intracellular [H+] on
metabolism
• maintaining a stable intracellular pH by:
− ‘Intracellular buffering’ (chemical, metabolic, organelles)
− Adjustment of arterial pCO2
− Loss of fixed acids from the cell into the extracellular fluid
pN  [H+] = [OH-]
pN=7.0 at 25˚C for pure H2O
pN=6.8 at 37˚C in cell
pH is constantly “impaired” by metabolism
− production of metabolic acids
• “volatile” acids (CO2 resp. H2CO3)
− intermediate metabolism of substrates (oxidation)
 CO2 + H2O  H2CO3
• “fixed” acids
− strong anorganic acids
 metabolism of proteins resp. AA
 sulphuric (Met, Cys)
 hydrochlorous (Arg, Lys)
 metabolism of nucl. acids
 phosphoric (DNA)
− lactate
 anaerobic glycolysis
− keton bodies
 metabolism of fatty acids  ketogenesis  acetoacetate
and hydroxybutyrate
− regulation of pH
• intracell. a extracell. buffers
• lungs - respiration (CO2)
• kidneys
− reabsorption of HCO3
−
excretion of H+
Chemical buffers and other types of H+ buffering
− (1) proteins ( amphoteric)
− H+ and CO2 diffuse across plasma membrane and are buffered
• ECF - albumin
− haemoglobin is strictly speaking ICF, but..!!
• ICF – cellular proteome
− (2) inorganic buffers
• ECF - carbonic acid / bicarbonate
− H2CO3 / HCO3
•
ICF - phosphoric acid / hydrogen phosphate
− H3PO4 / H2PO4
- + HPO4
2−
(3) transcellular exchange H+/K+
• changes of ABB influence potassium balance and
vice versa !!!
• hormonal effects!!
Henderson-Hasselbalch equation:
pH = 6.1 + log([HCO3
-] / 0.03 pCO2)
Organs involved in the regulation of ABB
− Equilibrium with plasma
− High buffer capacity
• Haemoglobin – main buffer for CO2
− Excretion of CO2 by alveolar ventilation: minimally 12,000 mmol/day
− Respiratory centre react in minutes, maximum of compensation in 12 – 24 hod, then decline of sensitivity
− Reabsorption of filtered bicarbonate: 4,000 to 5,000 mmol/day
− Excretion of the fixed acids (acid anion and associated H+)
• about 100 mmol/day
− CO2 production from complete oxidation of substrates
• 20% of the body’s daily production
− Metabolism of organic acid anions
• such as lactate, ketones and amino acids
− Metabolism of ammonium
• conversion of NH4
+ to urea in the liver consumes HCO3
•
production of glutamate = urine buffering
− Production of plasma proteins
• esp. albumin contributing to the anion gap
− Bone inorganic matrix consists of hydroxyapatite crystals (Ca10(PO4)6(OH)2]
• bone can take up H+ in exchange for Ca2+, Na+ and K+ (ionic exchange)
• release of HCO3
-, CO3
- or HPO4
2-
Regulation by resp. system - CO2
− differences in the stimulation of respiration by pCO2 ([H+] resp. in the
CSF) and/or pO2<60mmHg
− changes of alveolar ventilation
− disorders:
• acidemia
−  respiratory centre of the brain
−  alveolar ventilation
−  CO2
• alkalemia
−  respiratory centre of the brain
−   alveolar ventilation
−   CO2
paCO2
= VCO2
/ Va
Total CO2 carried
by blood:
= [HCO3] + [H2CO3]
+ [carbamino CO2]
+ [dissolved CO2]
Respiratory centre
− long-lasting respiratory acidosis
( PaCO2) decreases sensitivity of
resp. centre to PaCO2 and PaO2
becomes the main regulator
− administration of oxygen
therapeutically can sometimes
lead to worsening of resp.
acidosis or even to respiratory
arrest !!!
Renal system – fixed H+ & HCO3
−
Proximal tubular mechanisms:
• reabsorption of HCO3
- filtered at the
glomerulus
− carboanhydrase
− NHE-3 exchanger (reabsorption of
HCO3
- is coupled with reabsorption of
Na+)
• production of NH4
+
− from glutamine in prox. tubule with
parallel formation of HCO3

glutamine is a way of body to dispose of
nitrogen (in liver)
− most of NH4
+ recycles in the renal
medulla
− Distal tubular mechanisms:
• net excretion of H+
− normally 70mmol/day
− max. 700mmol/day
 together with proximal tubule excretion
of H+ could increase up to 1000x!!! (pH
of urine down to 4.5)
• reaction with HPO4
2- - formation of
“titratable acidity” (TA)
• addition of NH4
+ to luminal fluid
• reabsorption of remaining HCO3
-
Regulation of ABB in different parts of nephron
Na+/K+ ATP-ase
− electrogenic (ratio 3 Na+:2 K+)
− energy for secondary-active transports with Na+
Assessment of A-B balance
Arterial blood (interval) Venous blood
pH 7.40 7.38 - 7.42 7.33 - 7.43
H+ (nmol/l) 40 36 – 44
pCO2 (mmHg/kPa) 40 / 5.3 35 – 45 / 5.1 – 5.5 41 – 51
HCO3
- (mmol/l) 25 22 - 26 24 - 28
BE 2
AG (mEq/l) 12 10 - 14
Hb saturation (%) 95 80 – 95 70 – 75
pO2 (mmHg) 95 80 – 95 35 – 49
Disorders of A-B balance
− Acidosis vs. alkalosis: abnormal condition lowering or
raising arterial pH
• before activation of compensatory changes in response to the
primary aetiological factor
− Simple vs. mixed A-B disorders: single vs. multiple
aetiological factors
− Disorders are defined according to their effect on pH of ECF
− Primary cause  buffers  compensation  correction
Acidaemia: arterial pH<7.36 (i.e. [H+]>44 nM)
Alkalaemia: arterial pH>7.44 (i.e. [H+]<36 nM)
Causes
− Respiratory
• abnormal processes which tend to
alter pH because of a primary
change in pCO2 levels
− acidosis
− alkalosis
• buffering
− predominantly intracellular proteins
• compensation
− hyperventilation
 typically limited, hypoventlation is
often a cause of disorder
− renal
 delayed (days)
− Metabolic
• abnormal processes which tend to
alter pH because of a primary
change in [HCO3
-]
− acidosis
− alkalosis
• buffering
− predominantly bicarbonate system
• compensation
− hyperventilation
 rapid (min - hrs)
− renal
 delayed (days)
Respiratory acidosis (RAC)
− primary disorder is a pH due to PaCO2 (>40 mmHg), i.e. hypercapnia
− time course:
• acute (pH)
• chronic (pH or normalisation of pH)
− renal compensation – retention of HCO3
-, 3-4 days
− causes of RAC:
• decreased alveolar ventilation (most cases)
− the defect leading to this can occur at any level in the respiratory control mechanism
− the degree of hypoxemia corresponds with degree of alveolar hypoventilation
 enrichment of %O2 in inhaled air corrects solely “pure hypoventilation” !!!
• presence of excess CO2 in the inspired gas
− re-breathing of CO2-containing expired gas
− addition of CO2 to inspired gas
− insufflation of CO2 into body cavity (e.g. for laparoscopic surgery)
• increased production of CO2 by the body
− malignant hyperthermia, sepsis
paCO2 = VCO2 / VA
A rise in arterial pCO2 is such a potent
stimulus to ventilation that RAC will
rapidly correct unless some abnormal
factor is maintaining the hypoventilation
RA - inadequate alveolar ventilation
− Central respiratory depression & other CNS
problems
• drug depression of respiratory centre (e.g. by
opiates, sedatives, anaesthetics)
• CNS trauma, infarct, haemorrhage or tumour
• hypoventilation of obesity (e.g. Pickwick
syndrome)
• cervical cord trauma or lesions (at or above C4
level)
• high central neural blockade
• poliomyelitis
• tetanus
• cardiac arrest with cerebral hypoxia
− Nerve or muscle disorders
• Guillain-Barre syndrome
• Myasthenia gravis
• muscle relaxant drugs
• toxins e.g. organophosphates, snake venom
• various myopathies
− Lung or chest wall defects
• acute on COPD
• chest trauma -contusion, haemothorax
• pneumothorax
• diaphragmatic paralysis
• pulmonary oedema
• adult respiratory distress syndrome
• restrictive lung disease
• aspiration
− Airway disorders
• upper airway obstruction
• laryngospasm
• bronchospasm / asthma
− External factors
• Inadequate mechanical ventilation
Pathologic effects of hypercapnia
− CO2 rapidly diffuses across
membranes
• depression of intracellular
metabolism
− Extreme hypercapnia
• cerebral anaesthetic effects
(pCO2>100mmHg)
− Effect of hypoxemia
An arterial pCO2>90 mmHg is not compatible
with life in patients breathing room air:
pAO2 = [0.21x(760-47)]-90/0.8 = 37 mmHg
RAC – compensation and correction
− Acute RAC - buffering only!
• about 99% of this buffering occurs intracellularly
− proteins (haemoglobin and phosphates) are the most important intravascular buffers for CO2 but their concentration is low
relative to the amount of carbon dioxide requiring buffering
• the bicarbonate system is not responsible for any buffering of a respiratory acid-base disorder
− the system cannot buffer itself
• efficiency of compensatory hyperventilation is usually limited
− Chronic RAC - renal compensation
• bicarbonate retention
− takes 3 or 4 days to reach its maximum
• paCO2  pCO2 in proximal tubular cells  H+ secretion into the lumen:
−  HCO3 production which crosses the basolateral membrane and enters the circulation (so plasma [HCO3] increases)
−  Na+ reabsorption in exchange for H+
−  NH4 production and secretion to 'buffer' the H+ in the tubular lumen, parallel regeneration of HCO3
−
RAC treatment
• the pCO2 rapidly returns to normal with restoration of adequate alveolar ventilation
 treatment needs to be directed to correction of the primary cause if this is possible
• rapid fall in pCO2 (especially if the RA has been present for some time) can result in:
− severe hypotension
− “post hypercapnic alkalosis”
Respiratory alkalosis (RAL)
− causes: respiratory alkalosis is ALWAYS due to increased alveolar ventilation
(hyperventilation)
− low arterial pCO2 will be sensed by the central chemoreceptors and the hyperventilation will be inhibited
unless the patient’s ventilation is controlled
• (1) central causes (direct action via respiratory centre)
− head injury
− stroke
− anxiety-hyperventilation syndrome (psychogenic)
− other 'supra-tentorial' causes (pain, fear, stress, voluntary)
− various drugs (e.g. analeptics, propanidid, salicylate intoxication)
− various endogenous compounds
 toxins in patients with chronic liver disease
 progesterone during pregnancy
 cytokines during sepsis
• (2) hypoxaemia (act via peripheral chemoreceptors)
− respiratory stimulation via peripheral chemoreceptors
• (3) pulmonary causes (act via intrapulmonary receptors)
− decreases pulmonary compliance
 pulmonary embolism
 pneumonia
 asthma
 pulmonary oedema (all types)
• (4) iatrogenic
− excessive controlled ventilation
decrease in pCO2 that occurs
as a compensation for metabolic
acidosis is not a respiratory alkalosis
as it is not a primary process =
hypocapnia is not synonymous
with respiratory alkalosis !!!
Metabolic acidosis (MAC)
− Primary disorder is a pH due to HCO3
−
Pathophysiology:
•  fixed [H+] = high anion gap (AG)
• loss or  reabsorption of HCO3
- = normal AG
AG = [Na+] + [K+] - [Cl-] - [HCO3
-]
Aetiology of MAC
− High AG
• ketoacidosis
− diabetic
− alcoholism
− starvation
• lactic acidosis
− type A – hypoxia/hypo-perfusion
− type B – therapy (diabetes –
biguanids)
• renal failure
− acute
− chronic = uremia
• intoxication
− ethylenglycol
− methanol
− salycilates
− Normal AG (hyperchloremic)
• renal
− renal tubular acidosis
• GIT
− diarrhoea
− enterostomy
− drainage of pancreatic juice or bile
− intestinal fistula
Pathologic effects of MAC
− Respiratory
• hyperventilation
• shift of haemoglobin dissociation curve to
the right
− Cardiovascular
− Others
• increased bone resorption (chronic acidosis
only)
• shift of K+ out of cells causing hyperkalemia
Decreased
HCO3
stimulation of
SNS
- tachycardia
- vasoconstriction
HYPERVENTILATION
“KUSSMAUL RASPIRATION”
- depression of
contractility
- arythmias
(hyperkalemia)
Some effects of MAC are opposite
− Cardiovascular system
• pH>7.2 - effect of SNS stimulation dominates (catecholamines)
• pH<7.2
− direct inhibitory effect of [H+] on contractility
− vasodilatory effect of [H+]
− Hb dissociation curve
− Plasma [K+] reflects
• K+/H+ exchange
• glomerular filtration rate
− e.g. renal failure
• osmotic diuresis
− e.g. ketoacidosis
Common types of MAC - ketoacidosis
− Contributing disorders
• increased lipolysis in adipose tissue – mobilisation of NEFA
• increased production of keton bodies from acetyl CoA (lipolysis of TG) in liver (βhydroxybutyrate,
acetoacetate, acetone)
− their mutual ratio depends on ration NADH/NAD+
− Ketoacidosis is a consequence of
•  insulin/glucagon
•  catecholamines,  glucocorticoids
− (1) Diabetic
• hyperglycaemia + precipitating factors (stress, infection)
− lipolysis (insulin, catecholamines) – NEFA – dysregulation of NEFA metabolism in liver (insulin,
glucagon) – NEFA oxidation -acetyl CoA – ketogenesis
• clin. manifestation results from hyperglycaemia and ketoacidosis
− (2) Alcoholic
• typically chron. alcoholic several days after last binge, starving
 metabolism of ethanol to acetaldehyde and acetate consumes NAD+
 inhibition of gluconeogenesis favouring ketogenesis
− (3) Starvation
Common types of MAC - lactic acidosis
− Under normal circumstances entire lactate recycles
• lactate - pyruvate - complete oxidation
• gluconeogenesis (60% liver, 30% kidney)
• renal threshold (5 M/L) guarantees a complete reabsorption under the normal
circumstances
− Lactic acidosis
• increased production
− physical exercise, convulsions
 hepatic metabolism effective enough to prevent prolonged acidosis
• impaired metabolism of lactate
− type A = hypoxic
 shock (hypovolemic, distributive, cardiogennic), hypotension, anemia, heart failure, liver
failure, malignancy, … most often in combination !!!
− type B = inhibition of complete metabolism of lactate
 drugs – biguanids (inhibition of ox. phosphorylation in mitochondria)
Metabolic alkalosis (MAL)
− pH due to HCO3
−
Pathophysiology (according to the event. parallel change
of circulating volume):
• (A) hypovolemic MAL - compensatory retention of Na kidney
(aldosteron) leads to an increased excretion of H+
− loss of acidic ECF –prolonged vomiting or gastric juice drainage
− overuse of diuretic (apart from acetazolamide and K-sparing diuretics)
− congenit. hypochloremia
− some diarrhoeas (secretory type – Cl losses)
− diabetes insipidus
− Barter’s syndrome
• (B) normo-/hypervolemic MAL
− posthypercapnic
− increased alkali intake (antacids - NaHCO3, CaCO3)
− primary hyperaldosteronism
− secondarr hyperaldosteronism (e.g. renovascular hypertension)
− Cushing syndrome
− liver failure (tertiary hyperaldosteronism)
 combined with RAL due to stimulation of resp. centea by liver toxic metabolites
− compensation
• buffers
• retention of pCO2 by  stimulation of resp. centre
− however limited - ~ pCO2= 55mmHg hypoxia becomes regulatory parameter
• renal compensation limited as well because kidney either
pathogenetically contributes to MAL (B) or counteracts
hypovolémia (A) – circulus vitiosus