The Body Fluid Compartments: Extracellular and Intracellular Fluids; Edema

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Water is added to the body by two major sources

1) Ingested in the form of liquids or water in food = 2100 ml/day

2) synthesized in the body as a result of OXIDATION OF CARBS = 200 ml/day

total = 2300 ml/day

*Water intake is highly variable

Insensible Water Loss

-continuous loss of water by evaporation from the respiratory tract and diffusion through the skin
=700 ml/day under normal conditions

*this is independent of sweating

-through skin, it is minimized by the CHOLESTEROL FILLED CORNIFIED LAYER of the skin

-as air enters the respiratory tract it becomes saturated with moisture to a vapor pressure of 47 mm Hg before it is expelled (this happens because the vapor pressure of inspired air is usually less than 47 mm Hg
**In cold weather, the atmospheric vapor pressure decreased to nearly 0 ---> even greater loss of water

Other forms of water loss

1) Fluid loss in sweat - variable

2) Water loss in feces - normally very small

3) Water loss by the kidneys

Extracellular fluid (3 compartments)

1) interstitial fluid - 3/4

2) blood plasma - 1/4; noncellular part of the blood; it exchanges substances continuously with the interstitial fluid through the pores of the capillary membrane; These pores are highly permeable to almost all solutes in the extracellular fluid EXCEPT PROTEINS. Proteins remain higher in the plasma. Aside from the proteins, the compositions are mostly homogenous

3) transcellular fluid - fluid in synovial, peritoneal, pericardial, and intraocular spaces, as well as CSF

*accounts for ~20% of the body weight

5) Blood is also considered its own compartment - RBCs (40%) and plasma (60%)

As a person grows older, the percentage of total body weight that is fluid _____

-gradually decreases
-due to increased fat

Intracellular fluid compartment

-28-42 liters of fluid in the 100 trillion cells
-1 compartment
-40% of the total body weight in average person

Hematocrit

-fraction of blood composed of RBCs
-impossible to completely pack RBCs - therefore, about 3-4% of the plasma remains entrapped among the cells
-true hematocrit is only about 96% of the measured

polycythemia

-excess production of RBCs
-hematocrit can rise to .65

Donnan effect

-the concentration of POSITIVELY CHARGED IONS is slightly GREATER (~2%) in the plasma than in the interstitial fluid
*the plasma proteins have a net negative charge and, therefore tend to bind cations, such as sodium and potassium

-conversely, the anions tend to have a higher concentration in the interstitial fluid because the (-) charge of the proteins repel them

*for practical purposes the concentrations are considered to be EQUAL

Composition of ECF

-large amounts of sodium and chloride
-reasonable large amounts of bicarbonate ions
-small amounts of potassium, calcium, magnesium, phosphate, and organic acid ions

Cell membrane

-highly permeable to water but not to most of the electrolytes in the body

In contrast to the extracellular fluid, the intracellular fluid ____

-contains only small quantities of sodium and chloride ions and almost no calcium ions

**Instead it contains large amounts of POTASSIUM and PHOSPHATE IONS plus moderate quantities of magnesium and sulfate ions, all of which have low concentrations in the extracellular fluid

-also, cells contain large amounts of proteins, almost 4X as much as plasma

Measurement of Fluid Volumes in the different compartments

= the Indicator-Dilution Principle
-can be measured by placing an indicator substance in the compartment, allowing it to disperse throughout the compartment's fluid, and then analyzing the extent to which the substance becomes diluted

Indicator mass A = Indicator mass B

Volume B = Volume A x Concentration A / Concentration B

-based on conservation of mass principle

-indicator must be dispersed evenly throughout the compartment, only in the compartment being measured, indicator is not metabolized or excreted

Measurement of total body water

-radioactive water (tritium 3H2O) or heavy water (deutrium 2H20) can be used to measure total body water
-mix with total body water within a few hours after being injected
-use same dilution principle to measure total body water

*Another substance used to measure total body water is ANTIPYRINE - very lipid soluble and can rapidly penetrate cell membranes and distribute itself uniformly throughout the intracellular and extracellular compartments

Measurement of Extracellular fluid volume

-use radioactive sodium, radioactive chloride. radioactive iothalamate, thiosulfate ion, or inulin
-same principle
-sodium and others may diffuse into intracellular space so are given their own specific names (sodium space, inulin space, etc)

Intracellular Volume calculation

-can't be measured directly

Intracellular volume = Total Body water - Extracellular volume

Measurement of plasma volume

-use SERUM ALBUMIN labeled with radioactive iodine

-also dyes that avidly bind to plasma proteins, such as Evans blue dye

Calculation of Interstitial fluid volume

-not directly
-Interstitial fluid volume = Extracellular fluid volume - Plasma volume

Measurement of Blood Volume

-Total blood volume = plasma volume / 1 - hematocrit

-may also use RBCs labeled with radioactive material

osmoles

-total number of particles in solution is measured in OSMOLES
-One osmole = 1 mole of solute particles
-osmole is generally too large of a term so MILLIOSMOLE is used

Osmolality and Osmolarity

-Osmolality - osmoles/kilogram of water

-Osmolarity - osmoles/Liter of solution

*these terms are almost synonymous in dilute solutions
-it is easier to express body fluid quantities in liters rather than in kilograms of water --> more often see osmolarity

Hypertonic vs. Hypotonic solutions

Isotonic

-Hypertonic - sodium chloride solutions greater than ,9 %

-Hypotonic - sodium chloride solutions less than .9%

-examples = .9 % solution of sodium chloride; 5% glucose solutions

hyperosmotic and hypo-osmotic refer to solutions that _____

-have a higher or lower osmolarity, respectively, compared with the normal extracellular fluid, without regard for whether the solute permeates the cell membrane

** it usually takes about 30 mins to achieve osmotic equilibrium everywhere in the body after drinking water

Effect of adding Saline Solution to the ECF

1) If an isotonic solution is added to the ECF compartment - osmolarity does not change; only the extracellular fluid volume increases

2) Hypertonic solution added - ECF osmolarity increases and causes osmosis of water out of cells
-net effect is increase in extracellular volume, a decrease in intracellular volume, and a rise in osmolarity in both compartments

3) Hypotonic solution added - osmolarity of ECF decreases. Causes some osmosis of water into cells. **BOTH the intracellular and extracellular volume are increased, although the intracellular volume increases to a greater extent

Causes of Hyponatremia

-excess water or loss of sodium

*decreased plasma sodium concentration can result from loss of sodium chloride from the extracellular fluid or addition of excess water to the extracellular fluid

1) A primary loss of sodium chloride usually results in hyponatremia - dehydraion and is associated with decreased extracellular fluid volume
-causes = diarrhea and vomitting; overuse of diuretics that inhibit the ability of the kidneys to conserve sodium; certain types of sodium-wasting kidney disease; Addison's disease - results from decreased secretion of aldosterone (impairs ability of the kidneys to reabsorb sodium and can cause a modest degree of hyponatremia

2) Hyponatremia-overhydration
-excess ADH (SIADH); bronchogenic tumors

Consequences of Hyponatremia

-CELL SWELLING
-has profound effects on tissues and organs (ESPECIALLY THE BRAIN) --> brain cell edema and neurological symptoms including headache, nausea, lethargy, and disorientation
*If plasma sodium potassium falls below 115-120 mmol/L, brain swelling may lead to seizures, coma, permanent brain damage, and death

-Because the skull is rigid, the brain cannot increase its volume by more than about 10 percent without it being forced down the neck (herniation), which can lead to permanent brain injury and death.

**When hyponatremia evolves more slowly over several days, the brain and other tissues respond by transporting sodium, chloride, potassium, and organic solutes, such as glutamate, from the cells into the extracellular compartment. This attenuates osmotic flow of water into the cells and swelling of the tissues

** When hypertonic solutions are added too rapidly to correct hyponatremia, this can outpace the brain's ability to recapture the solutes lost from the cells and may lead to osmotic injury of the neurons that is associated with demyelination, a loss of the myelin sheath from nerves

Causes of Hypernatremia: water loss or excess sodium

1) Hypernatremia-dehydration
-Diabetes insipidus (inability to secrete ADH or inability to respond to ADH -nephrogenic diabetes insipidus); excessive sweating; dehydration (caused by water intake that is less than water loss)

2) Hypernatremia -overhydration
-Cushing's disease; primary aldosteronism
-this form is milder b/c water is also resorbed

Consequences of Hypernatremia

** Cell Shrinkage

-Hypernatremia is much less common than hyponatremia

-severe symptoms usually occur only with rapid and large increases in plasma sodium concentration above 158 to 160 mmol/L. One reason for this is that hypernatremia promotes intense thirst that protects against a large increase in plasma and extracellular fluid sodium

$$ However, severe hypernatremia can occur in patients with hypothalamic lesions that impair their sense of thirst, in infants who may not have ready access to water, or elderly patients with altered mental status.

Correction of Hypernatremia

-Correction of hypernatremia can be achieved by administering hypo-osmotic sodium chloride or dextrose solutions.
-also correct it SLOWLY
-The reason for this is that hypernatremia also activates defense mechanisms that protect the cell from changes in volume. These defense mechanisms are opposite to those that occur for hyponatremia and consist of mechanisms that increase the intracellular concentration of sodium and other solutes.

*Intracellular edema
-3 conditions are especially prone to cause intracellular swelling

1) Hyponatremia

2) depression of the metabolic systems of the tissues
-when blood flow to a tissue is decreased, the delivery of oxygen and nutrients is reduced. If the blood flow becomes too low to maintain normal tissue metabolism, the cell membrane ionic pumps become depressed. When this occurs, sodium ions that normally leak into the interior of the cell can no longer be pumped out of the cells and the excess intracellular sodium ions cause osmosis of water into the cells

3) lack of adequate nutrition to the cells

4) can also occur in inflammation due to increased cell membrane permeability allowing sodium and other ion to diffuse into the interior of the cell, with subsequent osmosis of water into the cells

Extracellular edema (2)

1) abnormal leakage of fluid from the plasma to the interstitial spaces across the capillaries -most common cause

2) failure of the lymphatics to return fluid from the interstitium back into the blood - lymphedema

Factors that increase capillary filtration

-Increased capillary filtration coefficient.
-Increased capillary hydrostatic pressure.
-Decreased plasma colloid osmotic pressure.

Lymphedema

-failure of the lymph vessels to return fluid and protein to the blood

**When lymph vessel function is greatly impaired, due to blockage or loss of the lymph vessels, edema can become especially severe because plasma proteins that leak into the interstitium have no other way to be removed. The rise in protein concentration raises the colloid osmotic pressure of the interstitial fluid, which draws even more fluid out of the capillaries

-Blockage of lymph flow can be especially severe with infections of the lymph nodes, such as occurs with infection by filaria nematodes (Wuchereria bancrofti), which are microscopic, threadlike worms. The adult worms live in the human lymph system and are spread from person to person by mosquitoes. People with filarial infections can suffer from severe lymphedema and elephantiasis and in men, swelling of the scrotum, called hydrocele. Lymphatic filariasis affects over 120 million people in 80 countries throughout the tropics and subtropics of Asia, Africa, the Western Pacific, and parts of the Caribbean and South America

*Lymphedema can also occur in certain types of cancer or after surgery in which lymph vessels are removed or obstructed.

Summary of Causes of Extracellular Edema

I. Increased capillary pressure
-Excessive kidney retention of salt and water
-Acute or chronic kidney failure
-Mineralocorticoid excess

II. High venous pressure and venous constriction
-Heart failure
-Venous obstruction
-Failure of venous pumps
(a) Paralysis of muscles
(b) Immobilization of parts of the body
(c) Failure of venous valves
-Decreased arteriolar resistance
Excessive body heat
Insufficiency of sympathetic nervous system
Vasodilator drugs

III. Decreased plasma proteins
-Loss of proteins in urine (nephrotic syndrome)
-Loss of protein from denuded skin areas
Burns
Wounds
-Failure to produce proteins
Liver disease (e.g., cirrhosis)
Serious protein or caloric malnutrition

IV. Increased capillary permeability
-Immune reactions that cause release of histamine and other immune products
-Toxins
-Bacterial infections
-Vitamin deficiency, especially vitamin C
-Prolonged ischemia
-Burns

V. Blockage of lymph return
Cancer
Infections (e.g., filaria nematodes)
Surgery
Congenital absence or abnormality of lymphatic vessels

Edema Caused by heart failure

**One of the most serious and most common causes of edema is heart failure. In heart failure, the heart fails to pump blood normally from the veins into the arteries; this raises venous pressure and capillary pressure, causing increased capillary filtration. In addition, the arterial pressure tends to fall, causing decreased excretion of salt and water by the kidneys, which increases blood volume and further raises capillary hydrostatic pressure to cause still more edema.
-also blood flow is reduced to the kidneys in heart failure --> stimulates renin secretion, adding to the edema

Pulmonary edema caused by left sided heart failure

In patients with left-sided heart failure but without significant failure of the right side of the heart, blood is pumped into the lungs normally by the right side of the heart but cannot escape easily from the pulmonary veins to the left side of the heart because this part of the heart has been greatly weakened. Consequently, all the pulmonary vascular pressures, including pulmonary capillary pressure, rise far above normal, causing serious and life-threatening pulmonary edema. When untreated, fluid accumulation in the lungs can rapidly progress, causing death within a few hours.

Edema caused by decreased kidney excretion of salt and water

* in kidney diseases that compromise urinary excretion of salt and water, large amounts of sodium chloride and water are added to the extracellular fluid. Most of this salt and water leaks from the blood into the interstitial spaces, but some remains in the blood. The main effects of this are to cause (1) widespread increases in interstitial fluid volume (extracellular edema) and (2) hypertension because of the increase in blood volume,

Edema caused by decreased plasma proteins

1) failure to produce normal amounts of proteins

2) leakage of proteins from the plasma caused the plasma colloid osmotic pressure to fall

3) loss of protein in the urine in certain kidney diseases = NEPHROTIC SYNDROME
-Multiple types of renal diseases can damage the membranes of the renal glomeruli, causing the membranes to become leaky to the plasma proteins and often allowing large quantities of these proteins to pass into the urine. When this loss exceeds the ability of the body to synthesize proteins, a reduction in plasma protein concentration occurs.

4) Cirrhosis of the LIVER
-the cells fail to produce enough plasma proteins
*also: the liver fibrosis sometimes compresses the abdominal portal venous drainage vessels
-->ASCITES

3 major safety factors prevent excessive fluid accumulation in the interstitial space:

(1) low compliance of the interstitium when interstitial fluid pressure is in the negative pressure range,
-compliance of the tissues, defined as the change in volume per millimeter of mercury pressure change, is low.
-as long as the interstitial fluid hydrostatic pressure is in the negative pressure range, small increases in interstitial fluid volume cause relatively large increases in interstitial fluid hydrostatic pressure, opposing further filtration of fluid into the tissues.
-normally the interstitial fluid hydrostatic pressure is -3, so it must increase by 3 mm Hg before large amounts of fluid will begin to accumulate in the tissues
- 3 mm Hg safety factor

(2) the ability of lymph flow to increase 10- to 50-fold, and
-7 mm Hg safety factor

(3) washdown of interstitial fluid protein concentration, which reduces interstitial fluid colloid osmotic pressure as capillary filtration increases.
-7 mm Hg safety factor


$$ Total safety factor is against edema is 17 mm Hg. This means that the capillary pressure in a peripheral tissue could theoretically rise by 17 mm Hg, or approximately DOUBLE the normal value, before marked edema would occur

Importance of interstitial gel

in normal tissues with negative interstitial fluid pressure, virtually all the fluid in the interstitium is in gel form. That is, the fluid is bound in a proteoglycan meshwork so that there are virtually no "free" fluid spaces larger than a few hundredths of a micrometer in diameter. The importance of the gel is that it prevents fluid from flowing easily through the tissues because of impediment from the "brush pile" of trillions of proteoglycan filaments.

Free fluid

hen interstitial fluid pressure rises to the positive pressure range, there is a tremendous accumulation of free fluid in the tissues. In this pressure range, the tissues are compliant, allowing large amounts of fluid to accumulate with relatively small additional increases in interstitial fluid hydrostatic pressure.

Pitting edema

Nonpitting edema

-accumulation of free fluid; positive pressure range; tissues are COMPLIANT;
-When this occurs, the edema is said to be pitting edema because one can press the thumb against the tissue area and push the fluid out of the area. When the thumb is removed, a pit is left in the skin for a few seconds until the fluid flows back from the surrounding tissues.

-occurs when the tissue cells swell instead of the interstitium OR when the fluid in the interstitium becomes clotted with fibrinogen so that it cannot move freely within the tissue spaces.

Proteoglycan filaments importance

-"Spacer" for the cells
-preventing rapid flow of fluid in tissues

*The proteoglycan filaments also prevent fluid from flowing too easily through the tissue spaces. If it were not for the proteoglycan filaments, the simple act of a person standing up would cause large amounts of interstitial fluid to flow from the upper body to the lower body. When too much fluid accumulates in the interstitium, as occurs in edema, this extra fluid creates large channels that allow the fluid to flow readily through the interstitium. Therefore, when severe edema occurs in the legs, the edema fluid often can be decreased by simply elevating the legs.

-the usual diffusion of nutrients to the cells and the removal of waste products from the cells are not compromised by the proteoglycan filaments of the interstitium.

Lymphatic vessels drain protein from the potential spaces

-Proteins collect in the potential spaces because of leakage out of the capillaries, similar to the collection of protein in the interstitial spaces throughout the body. The protein must be removed through lymphatics or other channels and returned to the circulation. Each potential space is either directly or indirectly connected with lymph vessels. In some cases, such as the pleural cavity and peritoneal cavity, large lymph vessels arise directly from the cavity itself.

Effusion

-edema fluid in the POTENTIAL SPACE

Potential Spaces

-pleural cavity, pericardial cavity, peritoneal cavity, and synovial cavity, including both the joint cavities and the bursae

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