Volume Regulation

Fluid Compartments

Size of the body fluid compartments:

TBW = 60% of body weight (for a 70 kg person – TBW = 42L)
TBW – 2/3 ICF (28L) and 1/3 ECF (14L)
ECF – ¼ intravascular fluid (plasma) and ¾ interstitial fluid

What Determines Size of Fluid Compartments?

(1) Osmolarity – the osmotic concentration of a solution expressed as osmoles of solute per liter of solution; if osmotic activity of one space changes then the osmolarity of a space separated by a permeable membrane will also change

osmolarity = 2[Na] + 2[K] + glucose/18 + BUN/2.8

(2) Tonicity – the osmotic pressure or tension of a solution, usually relative to that of blood; is a function of degree of restriction of osmotically active materials to a given space

Ex.Urea – Urea is freely permeable across most biomembranes and will distribute freely between compartments to achieve equilibrium. Therefore, it is not osmotically active and there is no effective tonicity and water does not move across the membrane

Albumin – In contrast, albumin is poorly diffusable so it will not distribute across the membranes to an equilibrium is achieved. Albumin exhibits effective tonicity and water will move across the membrane to the osmotic activity is equal. Glucose is also an effective osmole.

Volume Regulation

TBW dependends on: (1) Fluid intake (thirst, IV fluids); (2) Fluid loss (urine, GI, sweat)

Content ¹ Concentration (Content refers to the total amount while concentration is mass/volume)

Hypervolemia and hypovolemia are disorders of sodium content

The sodium content determines the size of the ECF Sodium is maintained in the ECF by the Na⁺/K⁺ ATPase and sodium is therefore tonically active. Since the total sodium content of the body is maintained at near constancy by the kidney, the ECF volume is nearly constant.

The size of the intracellular space is determined by the tonicity of the extracellular space As extracellular tonicity rises (ex. IV injection of albumin), water will move out of the intracellular compartment to achieve osmotic equilibrium, thus ß the size of the intracellular compartment.

Hyper-osmolarity and hypo-osmolarity are disorders of water content

While osmolality of the various fluid compartments is identical, the composition is not.

ECF: Na⁺, Cl^-,HCO3^-
ICF: K⁺, PO₄, protein

Osmolality Examples

(1) Addition of isotonic sodium (see figure below) – isotonic sodium is restricted to the ECF and the volume of the ECF Ý ; no shift between ICF and ECF; Ý in BP

(2) Addition of hypertonic sodium fluid (pure salt intake) (see figure below) – salt is restricted to the ECF and exterts its tonicity on the ICF leading to a shift of water from the ICF to the ECF. The osmolality of both spaces Ý , the ECF volume Ý and the ICF ß

(3) Addition of hypotonic fluid (pure water) (see figure below)– water will transiently ß ECF tonicity, but then diffuse into the ICF. Since the ICF is larger than the ECF, more of the water will end up in the ICF. Osmotic activity is ß in both compartments.

(4) Loss of isotonic sodium containing fluid (see figure below) – Tonicity is not altered and fluid does not flow out of the ICF. ß in ECF falls due to the direct loss of fluid.

Loss of hypertonic fluid (almost pure salt) (no figure) Þ ß tonicity of the of the ECF causing water to shift into the cells (ICF). ß osmolarity in both compartments, ß ECF and Ý ICF volume.

Loss of pure water (no figure) Þ Transient Ý in ECF tonicity causing water to move from the ICF to the ECF. Net effect is an overall Ý in osmolality with a ß in the size of both compartments

Volume Homeostasis – Physiology and Pathological States

Cell Physiology Within normal physiologic situations, there are complex regulatory systems that attempt to maintain cell volume so that even if a cell initially swells because of water moving into it, over time it can return to its normal size. Many cells are capable of extruding extra osmoles to decrease their intracellular volume.

Effective Arterial Blood Volume (EABV) EABV is a function of the intravascular volume, cardiac output an of the vascular capacitance. The kidney monitors the EABV to determine if sodium should be reabsorbed or excreted. A ß in ECF volume is always associated with a ß in EABV while and Ý in ECF may be associated with an Ý , normal or ß EABV. (EABV is a theoretical, not a measurable volume)

Sensors: carotid body and aorta - baroreceptors; atria - volume receptors; hypothalamus – osmolarity receptors; juxtaglomerular apparatus (JGA) – Na⁺ concentration

Neutral Sodium Balance Þ when sodium intake = sodium excretion; the set point is determined by sodium intake

Normal Response to Ý sodium intake: Positive Na⁺ balance Þ Na⁺ remains in the ECF due to Na⁺/K⁺ ATPase pumping Na⁺ out of the cell Þ Ý in both ECF volume and plasma osmolarity (P_osm) Þ fluid shifts from intracellular compartment to extracellular compartment to maintain isoosmolality (overall P_osm is still above baseline) Þ Ý P_osm leads to Ý thirst and Ý ADH Þ Ý water intake and Ý water reabsorption by collecting tubules Þ return to isoosmolality but Ý in extracellular fluid volume Þ volume/pressure sensors in aortic arch, carotid bodies, atria, and pulmonary vessels sense Ý volume Þ JG apparatus in kidney senses Ý pressure/volume Þ ß filtration fraction (FF), renin and sympathetic activity; Ý atrial natiuretic peptide all leading to a ß in sodium reabsorption and Ý renal sodium excretion

Normal Response to ß ECF volume: baroreceptors sense ß volume and activate renin, sympathetic nervous system and ADH Þ efferent vasoconstriction and Ý FF as well as Ý aldosterone release (Ý total peripheral resistance, RBF is ß ß but GFR ß resulting in Ý FF; angiotensin II constricts the efferent arteriole more than the afferent arteriole of the glomerulus; PGs are Ý ) Þ sodium and water reabsorption Þ repletion of ECFV leads to Ý Cardiac output, ß baroreceptor stimuli, ß renin/sympathetic nervous system activity and a return to baseline

Hypovolemic State and Hyponatremia

The kidney would like to excrete dilute urine to Ý the osmolarity of the plasma but it can’t because all the fluid is reabsorbed in the proximal tubule to compensate for the hypovolemic state. Only a very small amount of fluid is delivered to the distal tubule and the fluid that does arrive there is reabsorbed due to the Ý ADH levels.

Therapy is to treat volume disorder by adding normal saline. Ý in volume will ß the amount of fluid reabsorbed in the proximal tubule and Ý fluid in the distal tubule; the kidney can then excrete dilute urine and Ý osmolarity of plasma.

Volume Depletion States:

Causes: blood loss, vomiting, diarrhea, sweating, osmotic diuresis, diuretic use, diabetes mellitus/insipidus

Volume depletion implies that there is a ß ECF volume and a loss of total body sodium. This has nothing to do with serum sodium concentration which might be high, low or normal

Symptoms and signs of ß plasma volume: hypotension; Ý HR; dry cool skin; pale extremities; renal effects due to ß RBF with preservation of GFR (Ý FF) Þ ß urinary Na, Ý urinary osm, Ý urinary creatine (fractional excretion of sodium (FENa) < < 1%

Treatment: give saline

Volume Overload – Edema forming States - Edema is due to Ý interstitial fluid

Causes: ß plasma oncontic pressure, Ý intravascular pressure (primary sodium retention) and lymphatic or venous obstruction

Examples of Volume Overload and Edema formation:

Congestive Heart Failure:

Physiology: ß CO causes ß activation of baroreceptors and kidney perceives ß EABV Þ retention of fluid and Na⁺

Mechanism: edema from Na⁺ retention, Ý plasma volume, and Ý preload leading to Ý capillary hydrostatic pressure

Treatment: Ý heart contractility (ionotropic drugs like digoxin), ß afterload (ACE inhibitors), Ý fluid excretion (diuretics)

Cirrhosis

Physiology: scarred liver and portal HTN Þ Ý abdominal capillary pooling and ascities; peripheral vasodilation also occurs from AV shunts

Mechanism: kidney and baroreceptors perceive ß EABV and upregulate mechanisms to retain fluid; three is also ß albumin, due to ß synthesis in the liver, which ß plasma oncotic pressure Þ edema

Treatment: difficult; sodium restriction and diuretics

Nephrotic Syndrome

Physiology: renal disease associated with proteinuria (> 3.5 g/24h), hpyoalbuminemia, hyperlipidemia and edema

Cause: scarring of liver from alcohol, viral infection

Mechanism: loss of albumin in the urine leads to ß plasma oncontic pressure; primary pathophysiologic retention of sodium by the kidneys a manifestation of the underlying disease

Treatment: diuretics and treatment of underlying disease

Brain Function in Response to Hypernatremia and Hyponatremia

decreased Na⁺ in ECF causes fluid to move into the brain cells and causes cell swelling; brain can compensate by excreting osmoles from cells Þ ß tonicity of ICF and cause fluid to exit cell Þ ß cell size

when correcting hyponatremia you need to Ý the sodium concentration slowly to allow the brain cells to compensate by now Ý the tonicity of the intracellular fluid; only add 1meq Na⁺/hr

Osmoregulation vs. Volume Regulation

	Osmoregulation	Volume Regulation
What is sensed	Plasma osmolality	Effective tissue perfusion
How is it evaluated?	Serum [Na⁺]	Clinically (BP, HR, JVD, Rales)
Determined by:	Ratio between the amounts of solute and water present	Absolute amounts of solute and water present
Sensors	Hypothalamic osmoreceptors	Afferent arteriole Atria Carotid sinus
Effectors	ADH (turned on by high osmolality) Thirst	RAA ANP Norepinephrine ADH (turned on by low volume)
What is affected	Urine osmolality Water intake	Urinary sodium Thirst
Impaired regulation leads to:	Too much water – hyponatremia (low plasma [Na⁺]) Too little water – hypernatremia (high plasma [Na⁺])	Too much Na⁺ - edema Too little Na⁺ - volume depletion

Osmoregulation maintains the plasma Na⁺ concentration by affecting water excretion and water intake.

Volume regulation maintains tissue perfusion by affecting sodium excretion.