Chapter 24. Water and Electrolytes

Chloride Homeostasis

Chloride ions are strongly attracted to Na+, K+, and Ca2+. It would require great expenditure of energy to keep chloride ions separate from these cations, so chloride homeostasis is achieved primarily as a side effect of sodium homeostasis-as sodium is retained or excreted, chloride ions passively follow.

Functions of Chloride

Chloride ions are the most abundant anions of the ECF and thus make a major contribution to its osmolarity. Chloride ions are required for the formation of stomach acid (HCl), and they are involved in the chloride shift that accompanies carbon dioxide loading and unloading by the erythrocytes. By a similar mechanism explained later, chloride ions play a major role in the regulation of body pH.

Fluid Replacement Therapy

One of the most significant problems in the treatment of seriously ill patients is the restoration and maintenance of proper fluid volume, composition, and distribution among the fluid compartments. Fluids may be administered to replenish total body water, restore blood volume and pressure, shift water from one fluid compartment to another, or restore and maintain electrolyte and acid-base balance. Drinking water is the simplest method of fluid replacement, but it doesn't replace electrolytes. Heat exhaustion can occur when you lose water san salt in the sweat and replace the fluid by drinking plain water. Broths, juices, and sports drinks replace water, carbohydrates, and electrolytes. Patients who can't take fluids by mouth must be treated by alternative routes. Some fluid can be given by enema and absorbed through the colon. All routes of fluid administration other than the digestive tract are called parenteral routes. The most common of these is the IV route, but for various reasons, including inability to find a suitable vein, fluids are sometimes given by subcutaneous (SQ), intramuscular (IM), or other parenteral routes. Many kinds of sterile solutions are available to meet the fluid replacement needs of different patients. In cases of extensive blood loss, there may not be time to type and cross-match blood for a transfusion. The more urgent needs is to replenish blood volume and pressure. Normal saline (isotonic, 0.9% NaCl) is a relatively quick and simple means of raising blood volume while maintaining normal osmolarity, but it has significant shortcomings. It takes three to five times as much saline as whole to rebuild normal volume because much of the saline escapes the circulation into the interstitial fluid compartment or is excreted by the kidneys. In addition, normal saline can induce hypernatremia and hyperchloremia, because the body excretes the water but retains much of the NaCl. Hyperchloremia can, in turn, produce acidosis. Normal saline also lacks potassium, magnesium, and calcium. Indeed, it dilute those electrolytes that are already present and creates a risk of cardiac arrest from hypocalcemia. Saline also dilutes plasma albumin RBCs, creating still greater risk for patients who have suffered extensive blood loss. Nevertheless, the emergency maintenance of blood volume sometimes takes temporary precedence over these other considerations. Fluid therapy is also used to correct pH imbalances. Acidosis may be treated with Ringer's lactate solution, which includes sodium to rebuild ECF volume, potassium to rebuild ICF volume, lactate to balance the cations, and enough glucose to make the solution isotonic. Alkalosis can be treated with potassium chloride. This must be administered very carefully, because potassium ions can cause painful venous spasms, and even a small potassium excess can cause cardia arrest. High-potassium solutions should never be given to patients in renal failure or whose renal status is unknown, because in the absence of renal excretion of potassium, they can bring bring on lethal hyperkalemia. Ringer's lactate or potassium chloride also must be administered very cautiously, with close monitoring of blood pH, to avoid causing a pH imbalance opposite the one that was meant to be corrected. Too much Ringer's lactate causes alkalosis and too much KCl causes acidosis. Plasma volume expanders are hypertonic solutions or colloids that are retained in the bloodstream and draw interstitial water into it by osmosis. They include albumin, sucrose, mannitol, and dextran. Plasma expanders are also used to combat hypotonic hydration by drawing water out of swollen cells, averting such problems as seizures and coma. A plasma expander can draw several liters of water out of the intracellular compartment within a few minutes. Patients who can't eat are often given isotonic 5% dextrose (glucose). A fasting patient loses as much as 70-85g of protein per day from the tissues as protein is broken down to fuel the metabolism. Giving 100-150g of IV glucose per day reduces this by half and is said to have a protein-sparing effect. More than glucose is needed in some cases-for example, if a patient hasn't eaten for several days and can't be fed by nasogastric tube (due to lesions of the digestive tract, for example) or if large amounts of nutrients are needed for tissue repair following severe trauma, burns, or infections, In total parenteral nutrition (TPN), or hyperalimentation, a patient is provided with compete IV nutritional support, including a protein hydrolysate (amino acid mixture), vitamins, electrolytes, 20-25% glucose, and on alternate days, a fat emulsion. The water from parenteral solutions is normally excreted by the kidneys. If the patient has renal insufficiency, however, excretion may not keep pace with intake, and there is a risk of hypotonic hydration. IV fluids are usually given slowly, by IV drop, to avoid abrupt changes or overcompensation for the patient's condition. In addition to pH, the patient's heart rate, blood pressure, hematocrit, and plasma electrolyte concentrations are monitored, and the patient is examined periodically for respiratory sounds indicating pulmonary edema. The delicacy of fluid replacement therapy underscores the close relationships among fluids, electrolytes, and pH. It is dangerous to manipulate any one of these variables without close attention to the others. Parenteral fluid therapy is usually used for persons who are seriously ill. Their homeostatic mechanisms are already compromised and leave less room for error than in a healthy person.

Phosphates Imbalances

Phosphate homeostasis is not as critical as that of other electrolyte. The body can tolerate broad variations several times above or below the normal concentration with little immediate effect on physiology.

Hypermagnesemia (Mg2+ > 2.0 mEq/L)

Causes: Excessive intake, as in magnesium-based antacids. Deficiency of aldosterone or thyroid hormone. Renal failure. Clinical Manifestations: Muscle weakness, depressed reflexes, lethargy. Respiratory depression or failure. Hypotension, cardia arrest.

Water Gain and Loss

A person is in a state of fluid balance when daily gains and losses are equal and fluids are properly distributed in the body. We typically gain and lose about 2,500 mL/day. The gains come from two sources. One of these is metabolic water (about 200 mL/day), which is produced as a by-product of dehydration synthesis reactions and aerobic respiration: C6H12O6 + 6 O2 -> 6 CO2 + 6H2O The other source is preformed water, which is ingested in food (700 mL/day) and drink (1,600 mL/day). The routes of water loss are more varied: - 1,500 mL/day is excreted as urine. - 200 mL/day is eliminated in the feces. - 300 mL/day is lost in the expired breath. You can easily visualize this by breathing onto a cool surface such as a mirror. - 100 mL/day of sweat is secreted by a resting adult at an ambient air temperature of 20C (68F). - 400 mL/day is lost as cutaneous transpiration, water that diffuses through the epidermis and evaporates. This is not the same as sweat; it's not a glandular secretion. A simple way to observe it is to cup the palm of your gland for a minute against a cool nonporous surface such as a laboratory benchtop or mirror. When you take your hand away, you will notice the water that transpired through the skin and condensed on the surface, even in places that were not in contact with your skin. Water loss varies greatly with physical activity and environmental conditions. Respiratory loss increases in cold weather, for example, because cold air is drier and absorbs more body water from the respiratory tract. Hot, humid weather slightly reduces the respiratory loss but increases perspiration to as much as 1,200 mL/day. Prolonged, heavy work can raise the respiratory loss to 650 mL/day and perspiration to as much as 5L/day, though it reduces urine output by nearly two-thirds. Output through the breath and cutaneous transpiration is called insensible water loss because we're not usually aware of it. Sensible water loss is noticeable output, particularly through the urine and in case of sufficient sweating to produce obvious wetness of the skin. Obligatory water loss is output that is relatively unavoidable: expired air, cutaneous transpiration, sweat, fecal moisture, and the minimum urine output, about 400 mL/day, needed to prevent azotemia. Even dehydrated individuals cannot prevent such losses; thus, they become further dehydrated.

Functions of Magnesium

About 54% of the body's magnesium (Mg2+) is in the bone tissue and 45% in the intracellular fluid, especially in the skeletal muscles. Magnesium is the second most abundant intracellular cation after potassium. Most ICF Mg2+ is complexes with ATP, but Mg2+ is also a necessary cofactor for many enzymes, membrane transport proteins, and nucleic acids. Magnesium imbalances can therefore have wide-ranging effects on membrane transport, membrane electrical potentials, cell metabolism, and DNA replication.

Relationships Among Fluid, Electrolyte, and Acid-Base Imabalances

Acidosis->Hyperkalemia H+ diffuses into cells and displaces K+. As K+ leaves the ICF, K+ concentration in the ECF rises. Hyperkalemia->Acidosis Opposite from the above; high K+ concentration in the ECF causes less K+ to diffuse out of the cells than normally. H+ diffuses out to compensate, and this lowers the extracellular pH. Alkalosis->Hypokalemia H+ diffuse from ICF to ECF. More K+ remains in the ICF to compensate for the H+ loss, causing a drop in ECF K+ concentration. Hypokalemia->Alkalosis Opposite from the preceding line; low K+ concentration in the ECF causes K+ to diffuse out of cells. H+ diffuses in to replace K+, lowering the H+ concentration of the ECF and raising its pH. Acidosis->Hypochloremia More Cl- is excreted as NH4Cl to buffer the excess acid in the renal tubules, leaving less Cl- in the ECF. Alkalosis->Hyperchloremia More Cl- is reabsorbed from the renal tubules, so ingested Cl- accumulates in the ECF rather than being excreted. Hyperchloremia->Acidosis More H+ is retained in the blood to balance the excess Cl-, causing hyperchloremic acidosis. Hypovolemia->Alkalosis More Na+ is reabsorbed by the kidney. Na+ reabsorption is coupled to H+ secretion so more H+ is secreted and pH of the ECF rises. Hypervolemia->Acidosis Less Na+ is reabsorbed, so less H+ is secreted into the renal tubules. H+ retained in the ECF causes acidosis. Acidosis->Hypocalcemia Acidosis causes more Ca2+ to bind to plasma protein and citrate ions, lowering the concentration of free, ionized Ca2+ and causing symptoms of hypocalcemia. Alkalosis->Hypercalcemia Alkalosis causes more Ca2+ to dissociate from plasma protein and citrate ions, raising the concentration of free Ca2+

Causes of Acidosis - Metabolic

Acidosis: Excess production of organic acids as in diabetes mellitus and starvation; long-term anaerobic fermentation; hyperkalemia; chronic diarrhea; excessive alcohol consumption; drugs such as aspirin and laxatives Alkalosis: Rare but can result from chronic vomiting; overuse of bicarbonates (antacids); aldosterone hypersecretion

Causes of Acidosis - Respiratory

Acidosis: Hypoventilation, apnea, or respiratory arrest; asthma; emphysema; cystic fibrosis; chronic bronchitis; narcotic overdose Alkalosis: Hyperventilation due to pain or emotions such as anxiety; oxygen deficiency (as at high elevation)

Hyperkalemia (K+ > 5.5 mEq/L)

Causes: Kidney failure, burns, GI bleeding, crush injuries, rhabdomyolysis, hemolysis, transfusion with outdated blood, rapid IV KCl infusion, acidosis, hyperglycemia, aldosterone hyposecretion. Clinical Manifestations: Usually begin with cardiotoxic effects: ventricular fibrillation, bradycardia, cardia arrest. Irritability. Muscle weakness, flaccid paralysis. Nausea, vomiting, diarrhea.

Hypokalemia (K+ < 3.5 mEq/L)

Causes: Laxative or diuretic overuse; chronic vomiting or diarrhea; heavy sweating. Glucocorticoid or aldosterone hypersecretion. Alkalosis. Clinical Manifestations: Polyuria, polydipsia. Fatigue. Muscle pain, cramps, weakness, loss of muscle tone, depressed reflexes, tetanus, rhabdomyolysis. Cardiac hyperexcitability, arrhythmia. Nausea, vomiting, alkalosis, confusion. Respiratory arrest.

Sodium Homeostasis

An adult needs about 0.5g of sodium per day, whereas the typical American diet contains 3-7 g/day. Thus a dietary sodium deficiency is rare, and the primary concern is adequate excretion of the excess. This is one of the most important roles of the kidneys. There are multiple mechanisms for controlling sodium concentration, tied to its effects on blood pressure and osmolarity and coordinated by aldosterone, antidiuretic hormone, and the natriuretic peptides. Aldosterone, the "salt-retaining hormone", plays the primary role in adjustment of sodium excretion. Hyponatremia and hyperkalemia directly stimulate the adrenal cortex to secrete aldosterone, and hypotension stimulates its secretion by way of the renin-angiotensin-aldosterone mechanism. Only cells in the ascending limb of the nephron loop, the distal convoluted tubule, and the cortical part of the collecting duct have aldosterone receptors. Aldosterone, a steroid, binds to nuclear receptors and activates transcription of a gene for the Na+-k+ pump. In 10-30 minutes, enough Na+-K+ pumps are synthesized and installed in the plasma membrane to produce a noticeable effect- sodium concentration in the urine begins to fall and potassium concentration rises as the tubules reabsorb more sodium and secrete more hydrogen and potassium ions. Water and chloride passively follow sodium. Thus, the primary effects of aldosterone are that the urine contains less NaCl and more potassium and has a lower pH. An average adult male excretes 5g of sodium per day, but the urine can be virtually sodium-free when aldosterone level is high. Although aldosterone strongly influences sodium reabsorption, it has little effect on plasma sodium concentration because reabsorbed sodium is accompanied by a proportionate amount of water. Elevated blood pressure inhibits the renin-angiotensin-aldosterone mechanism. The kidneys then reabsorb almost no sodium beyond the proximal convoluted tubule (PCT), and the urine contains up to 30g of sodium per day. Aldosterone has only slight effects on urine volume, blood volume, and blood pressure in spite of the tendency of water to follow sodium osmotically. Even in aldosterone hypersecretion, blood volume is rarely more than 5-1)% above normal. An increase in blood volume increases blood pressure and glomerular filtration rate (GFR). Even though aldosterone increases the tubular reabsorption of sodium and water, this is offset by the rise in GFR and there is only a small drop in urine output. Antidiuretic hormone modifies water excretion independently of sodium excretion. Thus, unlike aldosterone, it can change sodium concentration. A high concentration of sodium in the blood stimulates the posterior lobe of the pituitary gland to release ADH> The kidneys then reabsorb more water, which slows down any further increase in blood sodium concentration. ADH alone cannot lower the concentration; this requires water ingestion to dilute the existing sodium. A drop in sodium concentration, by contrast, inhibits ADH release, More water is excreted, thereby raising the relative amount of sodium that remains in the blood. The natriuretic peptides inhibit sodium and water reabsorption and the secretion of renin and ADH. The kidneys then eliminate more sodium and water and lower the blood pressure. Angiotensin II, by contrast, activates the Na+-H+ antiport in the PCT and thereby increases sodium reabsorption and reduces urinary sodium output. Several other hormones also affect sodium homeostasis. Estrogen mimics the effect of aldosterone and causes women to retain water during pregnancy and part of the menstrual cycle. progesterone reduces sodium reabsorption and has a diuretic effect. High levels of glucocorticoids promote sodium reabsorption and edema. In some cases, sodium homeostasis is achieved by regulation of salt intake. A craving for salt occurs in people who are depleted of sodium-for example, by blood loss or Addison disease. Pregnant women sometimes develop a craving for salty foods. Salt craving is not limited to humans; many animals ranging from elephants to butterflies seek out wet salty soil where they can obtain this vital mineral.

Hypercalcemia (Ca2+ > 5.8 mEq/L)

Causes: Usually excess bone resorption; metastatic bone cancer and some other cancers; Paget disease; parathyroid hormone or vitamin D excess; thyroid hormone deficiency; immobility. Excessive use of calcium carbonate antacids. renal failure. Alkalosis. Clinical Manifestations: Anorexia, nausea, vomiting, constipation. Polydipsia, polyuria, nocturia. Depression, personality changes. Muscle weakness, depressed reflexes. Bone pain. Kidney stones. Cardiac arrhythmia, arrest. Confusion, delirium, stupor, coma.

Hypernatremia (Na+ > 145 mEq/L)

Causes: Water loss from chronic vomiting or diarrhea; burns; diuretics; excessive sweating; diabetes insipidus. Dehydration from lac of access to water or inadequate thirst and water consumption. IV hypertonic saline infusion. Excess dietary sodium. Corticosterone hypersecretion. Clinical Manifestations: Thirst and polyuria. Hypertension. Muscle spasms. CNS dysfunction due to brain cell shrinkage: confusion, lethargy or excitability, cerebral hemorrhage, seizures, coma.

Fluid Compartments

Body water is distributed among certain fluid compartments, areas separated by selectively permeable membranes and differing from each other in chemical composition. The major fluid compartments are: - 65% ICF - 35% ECF, subdivided into -- 25% tissue (interstitial) fluid -- 8% blood plasma and lymph, and -- 2% transcellular fluid, a catch-all category for cerebrospinal, synovial, peritoneal, pleural, and pericardial fluids; vitreous and aqueous humors of the eye; bile; and fluid in the digestive, urinary, and respiratory tracts. Fluid is continually exchanged between compartments by way of capillary walls and plasma membranes. Water moves by osmosis from the digestive tract to the bloodstream and by capillary filtration from the blood to the tissue fluid. From the tissue fluid, it may be reabsorbed by the capillaries, osmotically absorbed into cells, or taken up by the lymphatic system, which returns it to the bloodstream. because water moves so easily through plasma membranes, osmotic gradients between the ICF and ECF never last for very long. If a local imbalance arises, osmosis usually restores the balance within seconds so that intracellular and extracellular osmolarity are equal. If the osmolarity of the tissue fluid rises, water moves out of the cells; if it falls, water moves into the cells. Osmosis from one fluid compartment to another is determined by the relative concentration of solutes in each compartment. The most abundant solute particles by far are the electrolytes-especially sodium salts in the ECF and potassium salts in the ICF. Electrolytes play the principal role in governing the body's water distribution and total water content, the subjects of fluid and electrolyte balance are therefore inseparable.

Calcium Homeostasis

Calcium concentration is regulated chiefly by parathyroid hormone, calcitriol, and in children, calcitonin. these hormones work through their effects on bone deposition and resorption, intestinal absorption of calcium, and urinary excretion.

Functions of Calcium

Calcium lends strength to the skeleton, activates the sliding filament mechanism of muscle contraction, serves as a second messenger for some hormones and neurotransmitters, activates exocytosis of neurotransmitters and other cellular secretion, and is an essential factor in blood clotting. Cells maintain a very low intracellular calcium concentration because they require a high concentration of phosphate ions (for reasons discussed shortly). If calcium and phosphate were both very concentrated in a cell, calcium phosphate crystals would precipitate in the cytoplasm. To maintain a high phosphate concentration but avoid crystallization of calcium phosphate, cells pump out Ca2+ and keep it at a low intracellular concentration, or else sequester Ca2+ in the smooth ER and release it only when needed. Cells that store Ca2+ often have a protein called calsequestrin, which binds the stored Ca2+ and keeps it chemically unreactive.

Hypomagnesemia (Mg2+ < 1.5 mEq/L)

Causes: Alcoholism; intestinal malabsorption malnutrition. Chronic vomiting or diarrhea. Some diuretics. Lactation. Renal failure. Clinical Manifestations: Anorexia, lethargy, nausea, vomiting. Muscle weakness, tremor, spasms, fasciculations, tetanus. Hypertension, tachycardia, cardiac arrhythmia.

Hypocalcemia (Ca2+ < 4.5 mEq/L)

Causes: Dietary deficiency of calcium, magnesium, or vitamin D; vitamin D malabsorption; inadequate sunlight; parathyroid hormone deficiency or thyroid hormone excess. Chronic diarrhea. Pregnancy, lactation. Kidney disease. Acidosis. Clinical Manifestations: Bone weakness, osteomalacia, fractures. Muscle cramps, tremors, tetanus, seizures; laryngospasm and asphyxiation. Paresthesia. Heart failure.

Hyponatremia (Na+ < 130 mEq/L)

Causes: Excess consumption of plain water. Vomiting, diarrhea, burns, diuretics, polydipsia. Hormone imbalances including cortisol, aldosterone, or thyroid hormone deficiency; diabetes mellitus (with hyperglycemia); ADH excess. Kidney disease. Clinical Manifestations: Usually CNS dysfunction due to cerebral edema: headache, confusion, disorientation, personality changes, lethargy, stupor, seizures, coma. Pulmonary and cerebral edema. Tachycardia.

Electrolyte Balance

Electrolyte balance is a state in which the amount of electrolytes absorbed by the small intestine balances the amount lost from the body, chiefly through the urine, and in which electrolyte concentrations in the body fluids are regulated within homeostatic limits. Electrolytes are physiologically important for multiple reasons: They are chemically reactive and participate in metabolism, they determine the electrical potential (charge difference) across cell membranes, and they strongly affect the osmolarity of the body fluids and the body's water content and distribution. Strictly speaking, electrolytes are salts such as sodium chloride, not just sodium or chloride ions. In common usage, however, the individual ions are often loosely referred to as electrolytes. The major cations of the electrolytes are sodium (Na+), potassium (K+_, calcium (Ca2+), magnesium (Mg2+), and hydrogen (H+); the major anions are chloride (Cl-), bicarbonate (HCO3-), and phosphates (Pi). They typical concentrations of these ions in the blood plasma versus intracellular fluid. Notice that in spite of great difference sin electrolyte concentrations, the two fluid compartments have the same osmolarity (300 mOsm/L). Blood plasma is the most accessible fluid for measurements of electrolyte concentration, so excesses and deficiencies are defined with reference to normal plasma concentrations. Concentrations in the tissue fluid differ only slightly from those in the plasma. The prefix normo- denotes a normal electrolyte concentration (for example, normokalaemia), and hyper- and hypo- denote concentrations that are, respectively, sufficiently above or below normal to cause physiological disorders.

Forms of Fluid Imbalance

Fluid Deficiency: Volume depletion (hypovolemia) - reduced total body water - osmolarity: isotonic (normal) Dehydration (negative water balance) - reduced total body water - osmolarity: hypertonic (elevated) Fluid Excess: Volume excess - elevated total body water - isotonic (normal) Hypotonic hydration (positive water balance, water intoxication) - elevated total body water - hypotonic (reduced)

Fluid Deficiency

Fluid deficiency arises when output exceeds intake over a long enough period of time. The two kinds of deficiency-volume depletion and dehydration-differ in the relative loss of water and electrolytes and the resulting osmolarity of the ECF. This important distinction calls for different strategies of fluid replacement therapy. Volume depletion (hypovolemia) occurs when proportionate amounts of water and sodium are lost without replacement. Total body water declines but osmolarity remains normal. Volume depletion occurs in cases of hemorrhage, severe burns, and chronic vomiting or diarrhea. A less common cause is aldosterone hyposecretion (Addison disease), which results in inadequate sodium and water reabsorption by the kidneys. Dehydration (negative water balance) occurs when the body eliminates significantly more water than sodium, so the ECF osmolarity rises. The simplest cause of dehydration is lack of drinking water-for example, when stranded in a desert or at sea. It can be a serious problem for elderly and bedridden people who depend on others to provide them with water, especially for those who can't express their needs or who caretakers are insensitive to it. Diabetes mellitus, ADH hyposecretion (diabetes insipidus), profuse sweating, and overuse of diuretics are additional causes of dehydration. Cold weather can dehydrate a person just as much as hot weather. For three reasons, infants are more vulnerable to dehydration than adults: (1) Their high metabolic rate produces toxic metabolites faster, and they excrete more water to eliminate them. (2) Their kidneys are not fully mature and can't concentrate urine as effectively. (3) They have a greater ratio of body surface to volume; consequently, compared with adults, they lose twice as much water per kilogram of body weight by evaporation. Dehydration affects all fluid compartments. Suppose, for example, that you play a strenuous tennis match on a hot summer day and lose a liter of sweat. Where does this fluid come from? Most of it filters out of the bloodstream through the capillaries of the sweat glands. In principle, 1L of sweat would amount to about one-third of the blood plasma. However, as the blood loses water, its osmolarity rises and water from the tissue fluid enters the bloodstream to balance the loss. This raises the osmolarity of the tissue fluid, so water moves out of the cells to balance that. Ultimately, all three fluid compartments (the ICF, blood, and tissue fluid) lose water. To excrete 1L of sweat, about 300 mL of water would come from the tissue fluid and 700 mL from the ICF. Immoderate exercise without fluid replacement can lead to losses greater than 1L per hour. The most serious effects of fluid deficiency are circulatory shock due to loss of blood volume and neurological dysfunction due to dehydration of brain cells. Volume depletion by diarrhea is a major cause of infant mortality, especially under unsanitary conditions that lead to intestinal infections such as cholera.

Fluid Excess

Fluid excess is less common than fluid deficiency because the kidneys are highly effective at compensating for excessive intake by excreting more urine. Renal failure and other causes, however, can lead to excess fluid retention. Fluid excesses are of two types called volume excess and hypotonic hydration. In volume excess, both sodium and water are retained and the ECF remains isotonic. This can result from aldosterone hypersecretion or renal failure. In hypotonic hydration (also called water intoxication or positive water balance), more water than sodium is retained or ingested and the ECF becomes hypotonic. This can occur if you lose a large amount of water and salt through urine and sweat and you replace it by drinking plain water. Without a proportionate intake of electrolytes, water dilutes the ECF, makes it hypotonic,, and causes cellular swelling. ADH hypersecretion can cause hypotonic hydration by stimulating excessive water retention as sodium continues to be excreted. Among the most serious effects of either type of fluid excess are pulmonary and cerebral edema and death.

Regulation of Intake

Fluid intake is governed mainly by thirst. Dehydration reduces blood volume and pressure and raises blood osmolarity. The hypothalamus has at least three groups of neurons called osmoreceptors that respond to angiotensin II and rising osmolarity of the ECF-both of which are signs that the body has a water deficit. The osmoreceptors communicate with other hypothalamic neurons that produce antidiuretic hormone (ADH), thus promoting water conservation; they apparently communicate also with the cerebral cortex to produce a conscious sense of thirst. A mere 2-3% increase in plasma osmolarity makes a person intensely thirsty, as does 10-15% blood loss. When we're thirsty, we salivate less. These are two reasons for this: (1) The osmoreceptor response leads to sympathetic output from the hypothalamus that inhibits the salivary glands. (2) Saliva is produced primarily by capillary filtration, but in a dehydrated person, this is opposed by the lower capillary blood pressure and higher osmolarity of the blood. Reduced salivation produces a dry, sticky-feeling mouth and a desire to drink, but it is by no means certain that this is the primary motivation to drink. Some people don't secrete saliva, yet they don't drink any more than normal individuals except when eating, when they need water to moisten the food. The same is true of experimental animals that have the salivary ducts tied off. Long-term satiation of thirst depends on absorbing water from the small intestine and lowering the osmolarity of the blood. Reduced osmolarity stops the osmoreceptor response, promotes capillary filtration, and makes the saliva more abundant and watery. However, these changes require 30 minutes or longer to take effect, and it would be rather impractical if we had to drink that long while waiting to feel satisfied. Water intake would be grossly excessive, indeed potentially fatal. Fortunately, there are mechanisms that act more quickly to temporarily quench the thirst and allow time for the change in blood osmolarity to occur. Experiments with rats and dogs have isolated the stimuli that quench the thirst. One of these is cooling and moistening the mouth; rats drink less if their water is cool than if it is warm, and simply moistening the mouth temporarily satisfies an animal even if the water is drained from its esophagus before it reaches the stomach. Distension of the stomach and small intestine is another inhibitor of thirst. If a dog is allowed to drink while the water is drained from its esophagus but its stomach is inflated with a balloon, its thirst is satisfied for a time. If the water is drained away but the stomach isn't inflated, satiation doesn't last as long. Such fast-acting stimuli as coolness, moisture, and filling of the stomach stop an animal (and presumably a human) from drinking an excessive amount of liquid, buy they're effective for only 30-45 minutes. If they're not soon followed by absorption of water into the bloodstream, the thirst soon returns. Only a drop in blood osmolarity produces a lasting effect.

Fluid Sequestration

Fluid sequestration is a condition in which excess fluid accumulates in a particular location. Total body water and osmolarity may be normal, but the volume of circulating blood may drop to the point of causing circulatory shock. The most common form of sequestration is edema, the abnormal accumulation of fluid in the interstitial spaces, causing swelling of a tissue. Hemorrhage can be another cause of fluid sequestration; blood that pools and clots in the tissues is lost to circulation. yet another example is pleural effusion, caused by some lung infections, in which as much as several liters of fluid accumulate in the pleural cavity.

Fluid Balance in Cold Weather

Hot weather and profuse sweating are obvious threats to fluid balance, but so is cold weather. The body conserves heat by constricting the blood vessels of the skin and subcutaneous tissue, thus forcing blood into the deeper circulation. This raises the blood pressure, which inhibits the secretion of antidiuretic hormone and increases the secretion of natriuretic peptides. These hormonal changes increase urine output and reduce blood volume. In addition, cold air is relatively dry and increases respiratory water loss. This is why exercise causes the respiratory tract to "burn" more in cold weather than in warm. These cold-weather respiratory and urinary losses can cause significant hypovolemia. Furthermore, the onset of exercise stimulates vasodilation in the skeletal muscles. In a hypovolemic state, there may not be enough blood to supply them, and a person may experience weakness, fatigue, or fainting (hypovolemic shock). In winter sports and other activities such as snow shoveling, it is important to maintain fluid balance. Even if you don't feel thirsty, it is beneficial to take ample amounts of warm liquids such as soup or cider. Coffee, tea, and alcohol however, have diuretic effects that defeat the purpose of fluid intake.

Calcium Imbalances

Hypercalcemia (>5.8 mEq/L) can result from alkalosis, hyperparathyroidism, or hypothyroidism. It reduces the sodium permeability of plasma membranes and inhibits the depolarization of nerve and muscle cells. At concentrations >12 mEq/dL, hypercalcemia causes muscular weakness, depressed reflexes, and cardiac arrhythmia. Hypocalcemia (<4.5 mEq/L) can result from vitamin D deficiency, diarrhea, pregnancy, lactation, acidosis, hypoparathyroidism, or hyperthyroidism. It increases the sodium permeability of plasma membranes, causing the nervous and muscular systems to be overly excitable. Tetany occurs when calcium concentration drops to 6 mg/dL and may be lethal at 4 mg/dL (2 mEq/L) due to laryngospasm and suffocation.

Chloride Imbalances

Hyperchloremia (>105 mEq/L) is usually the result of dietary excess or administration of intravenous saline. Hypochloremia (<95 mEq/L) is usually a side effect of hyponatremia but sometimes results from hyperkalemia or acidosis. In the latter case, the kidneys retain potassium by excreting more sodium, and sodium takes chloride with it. The primary effects of chloride imbalances are disturbances in acid-base balance, but this works both ways-a pH imbalance arising from some other cause can also produce a chloride imbalance.

Compensation for Acid-Base Imbalances

In compensated acidosis or alkalosis, either the kidneys compensate for pH imbalances of respiratory origin, or the respiratory system compensates for pH imbalances of metabolic origin. Uncompensated acidosis or alkalosis is a pH imbalance that the body cannot correct without clinical intervention. In respiratory compensation, changes in pulmonary ventilation correct the pH of the body fluids by expelling or retaining CO2. If there is a CO2 excess (hypercapnia), pulmonary ventilation increases to expel CO2 and bring the blood pH back up to normal. If there is a CO2 deficiency (hypocapnia), ventilation is reduced to allow CO2 to accumulate in the blood and lower the pH to normal. This is very effective in correcting pH imbalances due to abnormal PCO2 but not very effective in correcting other causes of acidosis and alkalosis. In diabetic acidosis, foe example, the lungs can't reduce the concentration of ketone bodies in the blood, although one can somewhat compensate for the H+ that ketones release by increasing pulmonary ventilation and exhausting extra CO2. The respiratory system can adjust a blood pH of 7.0 back to 7.2 or 7.3 but not all the way back to the normal 7.4. Although the respiratory system has a very powerful buffering effect, its ability to stabilize pH is therefore limited. Renal compensation is an adjustment of pH by changing the rate of H+ secretion by the renal tubules. The kidneys are slower to respond to pH imbalances but better at restoring a fully normal pH. Urine usually has a pH of 5 to 6, but in acidosis it may fall as low as 4.5 because of excess H+, whereas in alkalosis it may rise as high as 8.2 because of excess HCO3-. The kidneys can't act quickly enough to compensate for short-term pH imbalances, such as the acidosis that could result from an asthmatic attack lasting an hour or two, or the alkalosis resulting form a brief episode of emotional hyperventilation. They are effective, however, at compensating for pH imbalances that last for a few days or longer. In acidosis, the renal tubules increase the rate of H+ secretion. The extra H+ in the tubular fluid must be buffered; otherwise the fluid pH could exceed the limiting pH and H+ secretion would stop. Therefore, in acidosis, the renal tubules secrete more ammonia to buffer the added H+, and the amount of ammonium chloride in the urine may rise to 7-10 times normal. In alkalosis, the bicarbonate concentration and pH of the urine are elevated. This is partly because there is more HCO3- in the blood and glomerular filtrate and partly because there isn't enough H+ in the tubular fluid to neutralize all the HCO3- in the filtrate.

Magnesium Imbalances

Magnesium imbalances are usually due to excessive loss from the body rather than dietary deficiency. Hypermagnesemia, an excess (>2.0 mEq/L), is rare except in renal insufficiency. It tends to have a sedative effect, with lethargy, muscle weakness, and weak reflexes; and it can cause respiratory depression or failure, hypotension due to lack of vasomotor tone, and flaccid, diastolic cardiac arrest. Hypomagnesemia, a plasma Mg2+ deficiency (<1.5 mEq/L), can result from intestinal malabsorption, vomiting diarrhea, or renal disease. It results in hyperirritability of the nervous and muscular systems; muscle tremors, spasms, or tetanus; hypertension resulting from excessive vasoconstriction; and tachycardia and ventricular arrhythmia.

Magnesium Homeostasis

Magnesium levels in the blood plasma normally range from 1.5-2.0 mEq/L, whereas intracellular concentrations are quite variable from one tissue to another, but range up to 40 mEq/L in skeletal muscle. Dietary intake of magnesium is typically 140-360 mg/day, but only 30-40% of it is absorbed by the small intestine and the rest passes through unused. Its intestinal absorption is regulated mainly by vitamin D. About two-thirds of the body's Mg2+ loss is via the feces and one-third via the urine. Retention or loss of plasma Mg2+ is regulated mainly by the thick segment of the ascending limb of the nephron loop, where about 70% of the filtered Mg2+ is reabsorbed; smaller amounts are reabsorbed in other segments of the nephron. Reabsorption is mainly by the paracellular route (between tubule epithelial cells), driven by the positive electrical potential of the tubular fluid repelling the positive magnesium ions. Parathyroid hormone governs the rate of reabsorption and is the primary regulator of plasm Mg2+ level.

Acid-Base Balance

Metabolism depends on the functioning of enzymes, and enzymes are very sensitive to pH. Slight deviations from the normal pH can shut down metabolic pathways as well as alter the structure and function of other macromolecules. Consequently, acid-base balance is one of the most important aspects of homeostasis. The blood and tissue fluid normally have a pH of 7.35-7.45. Acid-base balance is a state in which the pH of the body fluids is homeostatically regulated within this range. Such a narrow range of variation is remarkable considering that our metabolism constantly produces acid: lactic acid from anaerobic fermentation, phosphoric acids from nucleic acid catabolism, fatty acids and ketones from fat catabolism, and carbonic acid from carbon dioxide. These acids are a constant challenge to our enzyme functions, homeostasis, and survival. Here we examine buffering mechanisms for stabilizing internal pH and maintain acid-base balance.

Potassium Homeostasis

Potassium homeostasis is closely linked to that of sodium. Regardless of the body's state of potassium balance, about 90% of the potassium filtered by the glomerulus is reabsorbed by the PCT and the rest is excreted in the urine. Variations in potassium excretion are controlled later in the nephron by changing the amount of potassium returned to the tubular fluid by the distal convoluted tubule and cortical portion of the collecting duct (CD). When potassium concentration is high, these tubules secrete more potassium into the filtrate and the urine may contain more potassium than the glomerulus filters from the blood. When blood potassium level is low, the tubules secrete less. The distal convoluted tubule and collecting duct reabsorb potassium through their intercalated cells. Aldosterone regulates potassium balance along with sodium. A rise in potassium concentration stimulates the adrenal cortex to secrete aldosterone. Aldosterone stimulates renal secretion of potassium at the same time that it stimulates reabsorption of sodium. The more sodium there is in the urine, the less potassium, and vice versa.

Potassium Imbalances

Potassium imbalances are the most dangerous of all electrolyte imbalances. Hyperkalemia (>5.5 mEq/L) can have completely opposite effects depending on whether potassium concentration rises quickly or slowly. It can rise quickly when, for example, a crush injury or hemolytic anemia releases large amounts of potassium from ruptured cells. This can also result from a transfusion with outdated, stored blood because potassium leaks from erythrocytes into the plasma during storage. A sudden increase in extracellular potassium tends to make nerve and muscles cells abnormally excitable. Normally, potassium continually passes into and out of cells at equal rates-leaving by diffusion and reentering by the Na+-K+ pump. But in hyperkalemia, there is less concentration difference between the ICF and ECF, so the outward diffusion of potassium is reduced. More potassium remains in the cell than normal, and the plasma membrane therefore has a less negative resting potential and is closer to the threshold at which it will set off action potentials. This is a very dangerous condition that can quickly produce cardiac arrest. High-potassium solutions are sometimes used by veterinarians to euthanize animals and are used in some states as a lethal injection for capital punishment. Hyperkalemia can also have a slower onset stemming from such causes as aldosterone hyposecretion, renal failure, or acidosis. Paradoxically, if the extracellular potassium concentration rises slowly, nerve and muscle become less excitable. Slow depolarization of a cell inactivates voltage-gated sodium channels, and the channels don't become excitable again until the membrane repolarizes. Inactivated sodium channels cannot produce action potentials. Hypokalemia (<3.5 mEq/L) rarely results from a dietary deficiency, because most diets contain ample amounts of potassium; it can occur, however, in people with depressed appetites. Hypokalemia more often results from heavy sweating, chronic vomiting or diarrhea, excessive use of laxatives, aldosterone hypersecretion, or alkalosis. As ECF potassium concentration falls, more potassium moves from the ICF to the ECF. With the loss of these cations from the cytoplasm, cells become hyperpolarized and nerve and muscle cells are less excitable. This is reflected in muscle weakness, loss of muscle tone, depressed reflexes, and irregular electrical activity of the heart.

Functions of Potassium

Potassium is the most abundant cation of the ICF and is the greatest determinant of intracellular osmolarity and cell volume. Along with sodium, it produces the resting membrane potentials and action potential of nerve and muscle cells. Potassium is as important as sodium to the Na+-k+ pump and its functions of cotransport and thermogenesis (heat production). It is an essential cofactor for protein synthesis and some other metabolic processes.

The Protein Buffer System

Proteins are more concentrated than either bicarbonate or phosphate buffers, especially in the ICF. The protein buffer system accounts for about three-quarters of all chemical buffering in the body fluids. The buffering ability of proteins is due to certain side groups of tehir amino acid residues. Some have carboxyl side group (-COOH), which release H+ when pH begins to rise and thus lower pH: -COOH -> -COO- + H+ Others have amino side groups (-NH2), which bind H+ when pH falls too low, thus raising pH toward normal: -NH2 + H+ -> -NH3+

Functions of Sodium

Sodium is one of the principal ions responsible for the resting membrane potentials of cells, and the inflow of sodium through membrane channels is an essential event in the depolarization that underlies nerve and muscle function. Sodium is the principal cation of the ECF; sodium salts account for 90-95% of its osmolarity. Sodium is therefore the most significant solute in determining total body water and the distribution of water among fluid compartments. Sodium ions bound to the proteoglycans of cartilage retain water, ensuring that cartilages are well hydrated and able to act as effective cushions and shock absorbers. Sodium gradients across the plasma membrane provide the potential energy that is tapped to cotransport other solutes such as glucose, potassium, and calcium. The Na+-K+ pump is an important mechanism for generating body heat. Sodium bicarbonate (NaHCO3) plays a major role in buffering the pH of the ECF.

Phosphates Homeostasis

The average diet provides ample amount of phosphate, which is readily absorbed by the small intestine. Plasma phosphate concentration is usually maintained at about 4 mEq/L, with continual loss of excess phosphate by glomerular filtration. If plasma phosphate concentration drops much below this level, however, the renal tubules reabsorb all filtered phosphate. Parathyroid hormone increases the excretion of phosphate as part of the mechanism for increasing the concentration of free calcium ions in the ECF. Lowering the ECF phosphate concentration minimizes the formation of calcium phosphate and thus helps support plasma calcium concentration. Rates of phosphate excretion are also strongly affected by the pH of the urine.

The Bicarbonate Buffer System

The bicarbonate buffer system is a solution of carbonic acid and bicarbonate ions. As we can see in the carbonic acid reaction, carbonic acid (H2CO3) forms by the reaction of carbon dioxide with water, then dissociates into bicarbonate (HCO3-) and H+: CO2 + H2O <- -> H2CO3 <- -> HCO3- + H+ This is a reversible reaction. When it proceeds to the right, carbonic acid acts as a weak acid by releasing H+ and lowering pH. When the reaction proceeds to the left, bicarbonate acts as a weak base by binding H+, removing the ions from solution, and raising pH. At a pH of 7.4, the bicarbonate system wouldn't ordinarily have a particularly strong buffering capacity outside of the body. This is too far from its optimum pH of 6.1. If a strong acid was added to a beaker of carbonic acid-bicarbonate solution at pH 7.4, the preceding reaction would shift only slightly to the left. Much surplus H+ would remain and the pH would be substantially lower. In the body, by contrast, the bicarbonate system works quite well because the lungs and kidneys constantly remove CO2 and prevent an equilibrium from being reached. This keeps the reaction moving to the left, and more H+ is neutralized. Conversely, if there is a need to lower the pH, the kidneys excrete HCO3- and keep this reaction moving to the right, which elevates the H+ concentration of the ECF. Thus, you can see that the physiological and chemical buffers of the body function together in maintaining acid-base balance.

Summary of Imbalances

The causes and effects of electrolyte balances are so complex and interconnected as to be almost bewildering. They sometimes appear even contradictory, such as vomiting and diarrhea being among the causes or effects of both excess and deficiency of the same electrolyte. The table above therefore presents only a few of the especially common causes and effects. it omits many drugs and clinical procedures (such as gastric suction and fluid therapy) that can trigger imbalances. With few exceptions, we focus on spontaneous illnesses and patient behaviors-for example, the common problem of surreptitious overuse of laxatives and diuretics by people obsessed with weight loss, often throwing themselves into dangerous fluid, electrolyte, and acid-base disturbances. The clinical manifestations tabulated here include both signs (effects on a patient that can be observed byb others, such as seizures and coma) and symptoms (effects that can be felt only by the patient, such as headache, nausea, and malaise). The tabulated manifestations don't occur in every case of imbalance, or event most. They vary greatly with the magnitude of imbalance and from one population to another-such as infants, healthy adults, and people who are elderly or disabled-and imbalances are often asymptomatic or produce signs discovered only in blood work or electrocardiograms. Anorexia is lack of appetite. Malaise is a general sense of feeling uncomfortable or unwell, as if "coming down with something." Polydipsia means excessive thirst and drinking; polyuria, often associated with it, is excessive urine output. Nocturia is being awakened and having to urinate during the night and, sometimes, bed-wetting in children and incontinent adults. because electrolytes are so important in cell membrane potentials and nerve and muscle action, imbalances often have neuromuscular manifestations: paresthesia, abnormal sensation in the absence of external stimulation, such as numbness, burning, or tingling of the fingers; muscle fasciculations, involuntary twitching of individual fascicles of a muscle; or more extreme muscular reactions such as convulsions and tetanus-not the bacterial disease but the sustained contraction of a muscle, without relaxation. If it affects the respiratory muscles, tetanus can cause respiratory arrest; if it causes tightening of the laryngeal muscles, it can cause death by asphyxiation. Some electrolyte imbalances cause rhabdomyolysis, the death of muscle fibers, releasing their contents into the bloodstream, potentially clogging the kidneys with myoglobin and causing renal failure.

Acid-Base Imbalances in Relation to Electrolyte and Fluid Imbalances

The foregoing discussion once again underscores a point made early in this chapter-we can't understand or treat imbalances of fluid, electrolyte, or acid-base balance in isolation from each other, because each of these affects the other two itemizes and explains some of these interactions. This is by no means a complete list of how fluid, electrolytes, and pH affect each other, but it does demonstrate their interdependence. Note that many of these relationships are reciprocal-for example, acidosis can cause hyperkalemia, and conversely, hyperkalemia can cause acidosis

Functions of Phosphates

The inorganic phosphates (Pi) of the body fluids are an equilibrium mixture of phosphate [PO4(3-)], monohydrogen phosphate (HPO4 2-), and dihydrogen phosphate (H2PO4-) ions. Phosphates are relatively concentrated in the ICF, where they are generated by the hydrolysis of ATP and other phosphate compounds. They are a component of phospholipids, DNA, RNA, ATP, GTP, cAMP, creatine phosphate, and related compounds. Every process that depends on ATP depends on phosphate ions. Phosphates activate many metabolic pathways by phosphorylating enzymes and substrates such as glucose. They are also important as buffers that help stabilize the pH of the body fluids.

Renal Control of pH

The kidneys can neutralize more acid or base than either the respiratory system or the chemical buffers. they do so by varying the amount of acid eliminated in the urine. The essence of this mechanism is that the renal tubules secrete H_ into the tubular fluid, where most if it binds to bicarbonate, ammonia, and phosphate buffers. Bound and free H+ are then excreted in the urine. Thus the kidneys, in contrast to the lungs, actually expel H+ itself from the body. The other buffer systems only reduce its concentration by binding it to another chemical. Below shows how the renal tubules secrete and neutralize H+. The hydrogen ions are colored so you can trace them from the blood (step 1) to the tubular fluid (step 6). Notice that it is not a simple matter of transporting free H+ across the tubule cells; rather, the H+ travels in the form of carbonic acid and water molecules. The tubular secretion of H+ takes place at step 6, where the ion is pumped out of the tubule cell into the tubular fluid. This can happen only if there is a steep enough concentration gradient between a high H+ concentration within the cell and a lower concentration in the tubular fluid. If the pH of the tubular fluid drops any lower than 4.5, H+ concentration in the fluid is so high that tubular secretion ceases. Thus, pH 4.5 is the limiting pH for tubular secretion. In a person with normal acid-base balance, all bicarbonate ion (HCO3-) in the tubular fluid are consumed by neutralizing h+; thus there is no HCO3- in the urine. Bicarbonate ions are filtered by the glomerulus, gradually disappear from the tubular fluid, and appear in the peritubular capillary blood. it appears as if HCO3- is reabsorbed by the renal tubules, but this is not the case; indeed, the renal tubules are incapable of reabsorbing HCO3- directly. The cells of the proximal convoluted tubule, however, have carbonic anhydrase (CAH) on their brush borders facing the lumen. This breaks down the H2CO3 in the tubular fluid to CO2 + H2O (step 10). It is the CO2 that is reabsorbed, not the bicarbonate. For every CO2 reabsorbed, however, a new bicarbonate ion is formed in the tubule cell and released into the blood (step 5). The effect is the same as if the tubule cells had reabsorbed bicarbonate itself. Note that for every bicarbonate ion that enters the peritubular capillaries, a sodium ion does too. Thus, Na+ reabsorption by the renal tubules is part of the process of neutralizing acid. The more acid the kidneys excrete, the less sodium the urine contains. The tubules secrete somewhat more H+ than the available bicarbonate can neutralize. The urine therefore contains a slight excess of free H+, which gives it a pH of about 5-6. yet if all of the excess H+ secreted by the tubules remained in this free ionic form, the pH of the tubular fluid would drop far below the limiting pH of 4.5, and H+ secretion would stop. This must be prevented, and there are additional buffers in the tubular fluid to do so. The glomerular filtrate contains Na2HPO4 (dibasic sodium phosphate), which reacts with some of the H+. A hydrogen ion replaces one of the sodium ions in the buffer, forming NaH2PO4 (monobasic sodium phosphate). This is passed in the urine, and the displaced Na+ is transported into the tubule cell and from there to the bloodstream. In addition, tubule cells catabolize certain amino acids and release ammonia (NH3) as a product. Ammonia diffuses into the tubular fluid, where it acts as a base to neutralize acid. It reacts with H+ and Cl- (the most abundant anion in the glomerular filtrate) to form ammonium chloride (NH4Cl), which is passed in the urine. Since there is so much chloride in the tubular fluid, you may ask why H+ isn't simply excreted as hydrochloric acid (HCl). Why involve ammonia? The reason is that HCl is a strong acid-it dissociates almost completely, so most of its hydrogen would be in the form of free H_. The pH of the tubular fluid would drop below the limiting pH and prevent excretion of more acid-most of its hydrogen remains bound to it and doesn't lower the pH of the tubular fluid.

Sodium Imbalances

True imbalances in sodium concentration are relatively rare because sodium ecess or depletion is almost always accompanied by proportionate changes in water volume. Hypernatremia is a plasma sodium concentration in excess of 145 mEq/L. It can result from the administration of intravenous saline. Its major consequences are water retention, hypertension, and edema. Extreme hypertonicity shrinks cells, which damages their cytoskeleton, breaks DNA, and induces cell death by apoptosis. Hyponatremia (less than 130 mEq/L) is usually the result of excess body water rather than excess sodium excretion, as in the case mentioned earlier of a person who loses large volumes of sweat or urine and replaces it by drinking plain water. Usually, hyponatremia is quickly corrected by excretion of the excess water, but if uncorrected it produces the symptoms of hypotonic hydration described earlier.

Regulation of Output

The only way to control water output significantly is through variations in urine volume. It must be realized, however, that the kidneys can't completely prevent water loss, nor can they replace lost water or electrolytes. Therefore, they never restore fluid volume or osmolarity, but in dehydration they can support existring levels and slow down the rate of loss until water and electrolytes are ingested. To understand the effect of the kidneys on fluid and electrolyte balance, it is also important to bear in mind that if a substance is reabsorbed by the kidneys, it is kept in the body and returned to the ECF, where it will affect fluid volume and composition. If a substance is filtered by the glomerulus or secreted by the renal tubules and not reabsorbed, then it is excreted in the urine and lost from the body fluids. Changes in urine volume are usually linked to adjustments in sodium reabsorption. AS sodium is reabsorbed or excreted, proportionate amounts of water accompany it. The total volume of fluid remaining in the body may change, but its osmolarity remains stable. Controlling fluid balance by controlling sodium excretion is best understood in the context of electrolyte balance. Antidiuretic hormone (ADH), however, provides a mean of controlling water output independently of sodium. In true dehydration (defined shortly), blood volume declines and sodium concentration rises. The increases osmolarity of the blood stimulates the hypothalamic osmoreceptors, which stimulate the posterior pituitary to release ADH. In response to ADH, cells of the collecting ducts of the kidneys synthesize the proteins called aquaporins. When installed in the plasma membrane, these serve as channels that allow water to diffuse out of the duct into the hypertonic tissue fluid of the renal medulla. The kidneys then reabsorb more water and produce less urine. Sodium continues to be excreted, so the ratio of sodium to water in the urine increases (the urine becomes more concentrated). By helping the kidneys retain water, ADH slows down the decline in blood volume and the rise in its osmolarity. Thus, the ADH mechanism forms a negative feedback loop. Conversely, if blood volume and pressure are too high or blood osmolarity is too low, ADH release is inhibited. The renal tubules reabsorb less water, urine output increases, and total body water declines. This is an effective way of compensating for hypertension. Since the lack of ADH increases the ratio of water to sodium in the urine, it raises the sodium concentration and osmolarity of the blood.

Acids, Bases, and Buffers

The pH of a solution is determined solely by its hydrogen ion (H+). An acid is any chemical that releases H+ in solution. A strong acid such as hydrochloric acid (HCl) ionizes freely, gives up most of its hydrogen ions, and can markedly lower the pH of a solution. A weak acid such as carbonix acid (HwCO3) ionizes only slightly and keeps most hydrogen in a chemically bound form that doesn't affect pH. A base is any chemical that accepts H+. A strong base such as the hydroxide ion (OH-) has a strong tendency to bind H+ and raise the pH, whereas a weak base such as the bicarbonate ion (HCO3-) binds less of the available H+ and has less effect on pH. A buffer, broadly speaking, is any mechanism that resists pH changes by converting a strong acid or base to a weak one. The body has both physiological and chemical buffers. A physiological buffer is a system-namely, the respiratory or urinary system-that stabilizes pH by controlling the body's output of acids, bases, or CO2. Of all buffer systems, the urinary system buffers the greatest quantity of acid or base, but it requires several hours to days to exert an effect. The respiratory system exerts an effect within a few minutes but cannot alter the pH as much as the urinary system can. A chemical buffer is a substance that binds H+ and removes it from solution as its concentration begins to rise, or releases H+ into solution as its concentration falls. Chemical buffers can restore normal pH within a fraction of a second. They function as mixtures called buffer systems composed of a weak acid and a weak base. We have three major chemical buffer systems-the bicarbonate, phosphate, and protein systems. The amount of acid base that can be neutralized by a chemical buffer system depends on two factors: the concentration of the buffers and the pH of their working environment. Each system has an optimum pH at which it functions best; its effectiveness is greatly reduced if the pH of its environment deviates too far from this. The relevance of these factors will become apparent as you study the following buffer systems.

The Phosphate Buffer System

The phosphate buffer system is a solution of HPO4 2- and H2PO4-. It works in much the same way as the bicarbonate system. The following reaction can proceed to the right to liberate H+ and lower pH, or it can proceed to the left to bind H+ and raise pH: H2PO4- <- -> HPO4 2- + H+ The optimal pH for this system is 6.8, closer to the actual pH of the ECF (7.4). Thus, the phosphate buffer system has a stronger buffering effect than an equal amount of bicarbonate buffer. However, phosphates are much less concentrated in the ECF than bicarbonate, so they are less important in buffering the ECF. They are more important in the renal tubules and CIF, where not only are they more concentrated, but the pH is lower and closer to their functional optimum. In the ICF, the constant production of metabolic acids creates pH values ranging from 4.5-7.4, probably averaging 7.0.

Disorders of Acid-Base Balance

The picture represents acid-base balance with an instructive metaphor to show its dependence on the bicarbonate buffer system. At a normal pH of 7.4 the ECF has a 20:1 ratio of HCO3- to H2CO3. Excess hydrogen ions convert HCO3- to H2CO3 and tip the balance to a lower pH. A pH below 7.35 is considered to be a state of acidosis. On the other hand, a H+ deficiency causes H2CO3 to dissociate into H+ and HCO3- , thus tipping the balance to a higher pH. A pH above 7.45 is a state of alkalosis. Either of these imbalances has potentially fatal effects. A person can't live more than a few hours if the blood pH is below 7.0 or above 7.7, and a pH below 6.8 or above 8.0 is quickly fatal. In acidosis, H+ diffuses down its concentration gradient into cells, and to maintain electrical balance, K+ diffuse out. The H+ is buffered by intracellular proteins, so this exchange results in a net loss of cations from the cell. This makes the resting membrane potential more negative than usual (hyperpolarized) and makes nerve and muscle cells more difficult to stimulate this is why acidosis depresses the central nervous system and causes such symptoms as confusion, disorientation, and coma. In alkalosis, the extracellular H+ concentration is low. Hydrogen ions diffuse out of the cells and K+ diffuses in to replace them. he net gain in positive intracellular charges shifts the membrane potential closer to firing level and makes the nervous system hypoexcitable. Neurons fire spontaneously and overstimulate skeletal muscles, causing muscle spasms, tetanus, convulsions, or respiratory paralysis. Acid-base imbalances fall into two categories, respiratory and metabolic. Respiratory acidosis occurs when the rate of alveolar ventilation fails to keep pace with the body's rate of CO2 production. Carbon dioxide accumulates in the ECF and lowers its pH. This occurs in such conditions as emphysema, in which there is a severe reduction in the number of functional alveoli. Respiratory alkalosis results from hyperventilation, in which CO2 is eliminated faster than it is produced. Metabolic acidosis can result from increased production of organic acids, such as lactic acid in anaerobic fermentation and ketone bodies in alcoholism and diabetes mellitus. It can also result from the excessive ingestion of acidic drugs such as aspirin or from the loss of base due to chronic diarrhea or overuse of laxatives. Dying persons also typically exhibit acidosis. metabolic alkalosis is rare but can result from overuse of bicarbonates (such as oral antacids and intravenous bicarbonate solution) of from the loss of stomach acid by chronic vomiting.

Respiratory Control of pH

The respiratory buffer system adjusts the pH of the body fluids by raising or lowering the rate and depth of breathing. The equation for the bicarbonate buffer system shows that the addition of CO2 to the body fluids raises H+ concentration and lowers pH, while the removal of CO2 has the opposite effects. This is the basis for the strong buffering capacity of the respiratory system. Indeed, this system can neutralize two or three times as much acid as the chemical buffers can. Carbon dioxide is constantly produced by aerobic metabolism and is normally eliminated by the lungs at an equivalent rate. Rising CO2 concentration and falling pH stimulate peripheral and central chemoreceptors, which stimulate an increase in pulmonary ventilation. This expels excess CO2 and thus reduces H+ concentration. The free H+ becomes part of the water molecules produced by this reaction: HCO2- + H+ -> H2CO3 -> CO2 (expired) + H2O Conversely, a drop in H+ concentration raises pH and reduces pulmonary ventilation. This allows metabolic CO2 to accumulate in the ECF faster than it is expelled, thus lowering pH to normal. These are classic negative feedback mechanisms that result in acid-base homeostasis. Respiratory control of pH has some limitations, however, that are discussed later under acid-base imbalances.

Fluid Balance

We enter the world in rather soggy condition, having swallowed, excreted, and floated in amniotic fluid for months. At birth, a baby's weight is as much as 75% water; infants normally lose a little weight in the first day or two as they excrete the excess. Young adult men average 55-60%% water; women average slightly less because they have more adipose tissue, which is nearly free of water. Obese and elderly people are as little as 45% water by weight. The total body water (TBW) content of a 70kg (150lb) young male is about 40L.