Body fluid compartments

Water accounts for 50–60% of total body weight. This percentage varies with age, sex and body build, being less in women and the obese, as fat has a lower water content. Changes in total body water from one day to the next is, in an individual, reflected by changes in body weight. In a healthy, 70-kg male, total body water is approximately 42 litres, distributed between several compartments.
Two-thirds (28 litres) is intracellular fluid (I CF);
the remainder is extracellular fluid (ECF), comprising the interstitial fluid (10.5 litres) and the vascular compartment (3.5 litres).
There is no barrier to the passage of water between the extracellular and intracellular compartments as the distribution of water is governed by osmotic forces and all compartments have the same osmolality (280- 290 mosmol kg”). The major intracellular solute is potassium, balanced largely by phosphate and ionic protein, whilst the major extracellular solute is sodium chloride. Osmolality is determined by the concentration of osmotically active particles. Fully ionized (dissociated) molecules (e.g. NaCl) have twice the osmolality of undissociated particles (urea, glucose). The major determinant of plasma osmolality is sodium concentration: plasma osmolality can be approximated as (2 x [Na+l) + [urea] + [glucose], unless there is an unmeasured osmotically active substance present. For instance, plasma alcohol or ethylene glycol concentration can be estimated by subtracting calculated from measured osmolality.
The distribution of extracellular water between the vascular and extravascular (interstitial space) is determined by the equilibrium between hydrostatic and oncotic pressures (Fig. 10.1). The composition of intracellular and extracellular fluids.

Distribution of water between the vascular and extravascular
Distribution of water between the vascular and extravascular

the relative effect of the addition of identical volumes of water, saline and colloid solutions on the different compartments. Thus, 1 litre of water given intravenously as 5% dextrose is distributed equally into all compartments, whilst 1 litre of 0.9% saline remains in the extracellular compartment. The latter is thus the correct treatment for extracellular water depletion-sodium keeping the water in this compartment. The addition of 1 litre of colloid with its high oncotic pressure stays in the vascular compartment and is the treatment for hypovolaemia. Regulation of extracellular volume The extracellular volume is controlled by the total body content of sodium. Sodium is ‘diluted’ by water to keep it at the right concentration.
It is essential to distinguish between the concentration of sodium in the ECF (in practice the plasma sodium) and the amount of sodium. Concentration only implies the relative amounts of sodium to water and does not suggest the absolute amounts or volumes of either. Control of the body’s sodium is exerted by tight control over renal excretion. This is achieved by activation of receptors which respond to extracellular volume rather than the change in sodium concentration. These ‘volume’ receptors can be divided into extrarenal and intrarenal baroreceptors.

EXTRARENAL. These are located in the vascular tree in the left atrium and major thoracic veins and also in the sinus body and aortic arch. These volume receptors respond to a slight reduction in effective circulating volume and result in increased sympathetic nerve activity and a rise in catecholamines. In addition volume receptors in the cardiac atria control the release of a powerful natriuretic hormone-atrial natriuretic peptide (ANP)- from granules located in the atrial walls.
INTRARENAL. Receptors in the walls of the afferent glomerular arterioles respond, via the juxtaglomerular apparatus, to changes in renal perfusion, and control the activity of the renin-angiotensin-aldosterone system. In addition sodium concentration in the distal tubule and sympathetic nerve activity alter renin release from the juxtaglomerular cells. Prostaglandins 12 and E2 are also generated within the kidney in response to angiotensin II, acting to maintain glomerular filtration rate and sodium and water excretion, modulating the sodiumretaining effect of this hormone

Electrolyte composition of intracellular and extracellular fluids.
Electrolyte composition of intracellular and
extracellular fluids.
The relative effects of addition of 1 litre of water
The relative effects of addition of 1 litre of water

The final common pathway for all the regulatory systems discussed is to increase or decrease the renal excretion of sodium in the event of an increase or decrease in effective circulating blood volume. An increase in the reabsorption of salt, with concomitant retention of water (due to a change in osmolality) expands the vascular and interstitial compartments while increased sodium excretion has the opposite effect..

Regulation of extracellular volume in health and disease.
Regulation of extracellular volume in health and

Regulation of body water content

Body water homeostasis is effected by thirst and the urine concentrating and diluting functions of the kidney. These in turn are controlled by intracellular osmoreceptors, principally in the hypothalamus, to some extent by volume receptors in capacitance vessels close to the heart, and via the renin-angiotensin system. Of these, the major and best-understood control is via osmoreceptors. An increase in intracellular osmolality-for example after water deprivation-stimulates both thirst and release of anti-diuretic hormone (ADH) from the posterior pituitary. Thirst stimulates increased water intake while ADH increases the reabsorption of water from the tubular fluid by its action on the distal tubules of the kidney. This causes a reduction in the urine output. The increased intake of water and reduced urinary excretion results in a net gain of water that returns body fluid osmolality to normal. A decrease in intracellular osmolality in the osmoreceptors has the reverse effect. By this method the amount of water in body fluid is adjusted to ensure normal osmolality in the face of varying increase or loss of water or solute.
In addition non-osmotic stimuli may cause ADH release even if serum osmolality is normal or even low. These include hypovolaemia, stress (e.g. surgery, trauma), psychiatric disturbance and nausea. Increased extracellular volume.
Increased extracellular volume occurs in numerous disease states. The physical signs depend on the distribution of excess volume and on whether the increase is local or systemic. According to Starling principles, distribution depends on venous tone, which determines the capacitance of the blood compartment and thus hydrostatic pressure
• capillary permeability
• oncotic pressure-mainly dependent on serum albumm
• lymphatic drainage
Depending on these factors, fluid accumulation may result in expansion of interstitial volume, blood volume, or both.


Peripheral oedema is caused by expansion of the extracellular volume by at least 2 lit res (15%). The ankles are normally the first part of the body to be affected, although the ankles may be spared in patients with lipodermatosclerosis (where the skin is tethered and cannot expand to accommodate the oedema). Oedema may be noted in the face, particularly in the morning, and in a patient in bed oedema may accumulate in the sacral area. Expansion of the interstitial volume also causes pulmonary oedema, pleural effusion, pericardial effusion and ascites. Expansion of the blood volume causes a raised jugular venous pressure, cardiomegaly, added heart sounds and a raised arterial blood pressure in certain circumstances.


Extracellular volume expansion is due to sodium chloride retention. Increased salt intake does not normally cause volume expansion because of rapid homeostatic mechanisms which increase salt excretion. However, a rapid intravenous solution of a large volume of saline will cause volume expansion. Thus most causes of extracellular volume expansion are associated with renal sodium chloride retention:
HEART FAILURE: due to increased venous pressure causing oedema formation, activation of the reninangiotensin- aldosterone system, and increased activity of the renal sympathetic nerves.
HYPOALBUMINAEMIA : the major mechanism is loss of plasma on cotic pressure leading to loss of water from the vascular space to the interstitial space. This activates the renin-angiotensinaldosterone system. However, other factors may be involved as in the nephrotic syndrome measured plasma volume may be normal, decreased, or increased. There is some evidence that the nephrotic syndrome itself alters renal sodium handling.
HEPATIC CIRRHOSIS: the mechanism is again complex, but involves peripheral vasodilatation, possibly due to nitric oxide with activation of the renin-angiotensinaldosterone system causing sodium retention.
RENAL IMPAIRMENT: decreased glomerular filtrationrate decreases renal capacity to excrete sodium. This may be acute, as in the acute nephritic syndrome, or may occur as part of the presentation ofchronic renal failure. In end-stage renal failure extracellular volume is controlled by the balance between salt intake and its removal by dialysis. Mild sodium retention can also be caused by oestrogens which have a weak aldosterone-like effect. This produces weight gain in the premenstrual phase.
Numerous other drugs may cause renal sodium retention, particularly in patients whose renal function is already impaired:
• Mineralocorticoids and liquorice (which potentiates the sodium-retaining action of cortisol) have aldosterone- like actions
• NSAIDs, in the presence of activation of the reninangiotensin- aldosterone system by heart failure, cirrhosis and renal artery stenosis Substantial amounts of sodium and water may accumulate in the body without clinically obvious oedema or evidence of raised venous pressure. In particular, several litres may accumulate in the pleural space or as ascites; these spaces are then referred to as ‘third spaces’. Bone may also act as a ‘sink’ for sodium and water.

Other causes of oedema

Initiation of insulin treatment for type 1 diabetes and refeeding after malnutrition are both associated with the development of transient oedema; the mechanism is complex. Oedema may also result from increased capillary pressure due to relaxation of precapillary arterioles; the best example is the peripheral oedema caused by dihydropyridine calcium channel blockers such as nifedipine. Oedema may also be caused by increased interstitial oncotic pressure as a result of increased capillary permeability to proteins. This may occur as part of a rare complement-deficiency syndrome; as a result of septicaemia;
with therapeutic use of interleukin-2 in cancer chemotherapy; or in ovarian hyperstimulation syndrome. IDIOPATHIC OEDEMA OF WOMEN, by definition, occurs in women without heart failure, hypoalbuminaemia, renal or endocrine disease. Oedema is intermittent and often worse in the premenstrual phase. The condition remits after the menopause. Patients complain of swelling of the face, hands, breasts and thighs and a feeling of being bloated. Sodium retention during the day and increased sodium excretion during recumbency are characteristic; an abnormal fall in plasma volume on standing caused by increased capillary permeability to proteins may be the cause of this. The oedema may respond to diuretics, but returns when they are stopped. A similar syndrome of diuretic-dependent sodium retention can be caused by abuse of diuretics, for instance as part of an attempt to lose weight, but not all women with idiopathic oedema admit to having taken diuretics, and the syndrome was described before diuretics were introduced for clinical use.
LOCAL INCREASE IN OEDEMA does not reflect disturbances of extracellular volume control per se, but can cause clinical confusion, e.g. ankle oedema due to venous damage following thrombosis or surgery, ankle or leg oedema due to immobility, oedema of the arm due to subclavian thrombosis, facial oedema due to superior vena caval obstruction. Local loss of oncotic pressure may result from increased capillary permeability to proteins, caused by inflammatory mediators including histamine and interleukins, e.g. bee stings. Lastly, local loss of lymphatic drainage causes lymphoedema.


The underlying cause should be treated where possible. For instance, treat heart failure, or withdraw offending drugs, e.g. NSAIDs. Sodium restriction has a limited role, but is useful in patients who are resistant to diuretics. Sodium intake can easily be reduced to approximately 100 mmol daily; reductions below this are often difficult to achieve without affecting the palatability of food. Manoeuvres which increase venous return stimulate salt and water excretion by effects on cardiac output and ANP release. This is the rationale for strict bed rest in congestive cardiac failure. Water immersion also causes redistribution of blood towards the central veins, but is seldom of practical use. Venous compression stockings or bandages may help to mobilize oedema in heart failure. The mainstay of treatment is the use of diuretic agents, which increase sodium, chloride and water excretion in the kidney. These agents act by interfering with membrane ion pumps which are present on numerous cell types, but most achieve specificity for the kidney by being secreted into the proximal tubule, resulting in much higher concentrations in the tubular fluid than in other parts of the body.

Types and clinical uses of diuretics.
Types and clinical uses of diuretics.

Clinical use of diuretics

Loop DIURETICS are widely used, potent diuretics which are useful in the treatment of any cause of systemic extracellular volume overload. They stimulate excretion of both sodium chloride and water, and are useful in stimulating water excretion in states of relative water overload.
They also act by causing increased venous capacitance, resulting in rapid clinical improvement in patients with left ventricular failure, preceding the diuresis. Unwanted effects include:
• Urate retention causing gout
• Hypokalaemia
• Hypomagnesaemia
• Decreased glucose tolerance
• Allergic tubulo-interstitial nephritis and other allergic reactions
• Myalgia (especially with bumetanide)
• Ototoxicity (due to an action on sodium pump activity in the inner earl-particularly frusemide
• Interference with excretion oflithium, resulting in toxicity In most situations there is little to choose between the drugs in this class. Ethacrynic acid is now very seldom used because of ototoxicity. Bumetanide has a better oral bioavailability, particularly in patients with severe peripheral oedema, and may have more beneficial effects on venous capacitance in left ventricular failure than frusemide. It may cause severe muscle cramps when used in high doses.

THIAZ IDE DIURETIC S are weaker diuretics than loop diuretics. They cause relatively more urate retention, glucose intolerance and hypokalaemia. They interfere with water excretion and may cause hyponatraemia, particularly if combined with amiloride or triamterene. This effect is clinically useful in diabetes insipidus. Thiazides reduce peripheral vascular resistance by mechanisms which are not completely understood but which do not appear to depend on their diuretic action, and are widely used in the treatment of essential hypertension. They are also used extensively in mild to moderate cardiac failure. Thiazides reduce calcium excretion. This effect is useful in patients with idiopathic hypercalciuria, but may cause hypercalcaemia. Numerous agents are available, with varying half-lives but little else to choose between them. Metolazone is not dependent for its action on glomerular filtration, and therefore retains its potency in renal impairment.
POTASSIUM-SPARING DIURETICS are relatively weak and are most often used in combination with thiazides or loop diuretics to prevent potassium depletion. These are of two types. Spironolactone, an aldosterone antagonist, competes with aldosterone in the collecting ducts reducing sodium absorption. Amiloride and triamterene inhibit sodium uptake in collecting duct epithelial cells and reduce renal potassium excretion.
CARBONIC ANHYDRASE INHIBITORS are relatively weak diuretics and are seldom used except in the treatment of glaucoma. They may cause metabolic acidosis and hypokalaemia.
RESISTANCE TO DIURETICS may occur as a result of:
• Poor bioavailability
• Reduced GFR, which may be due to decreased circulating volume despite oedema (e.g. nephrotic syndrome, local causes of oedema) or intrinsic renal disease
• Activation of sodium-retaining mechanisms, particularly aldosterone
Intravenous administration may establish a diuresis. High doses of loop diuretics may be required to achieve adequate concentrations in the tubule if GFR is depressed: the daily dose of frusemide must be limited to a maximum of 2 g for an adult, because of ototoxicity. Intravenous albumin solutions restore plasma oncotic pressure temporarily in the nephrotic syndrome and may allow mobilization of oedema. Combinations of different classes of diuretics are extremely helpful in patients with resistant oedema. A loop diuretic plus a thiazide inhibits two major sites of sodium reabsorption; this effect may be further potentiated by addition of a potassium-sparing agent. Metolazone in combination with a loop diuretic is particularly useful in refractory congestive cardiac failure, because its action is less dependent on glomerular filtration. However, this potent combination can cause severe electrolyte imbalance.
Both aminophylline and dopamine increase renal blood flow and may be useful in refractory cardiogenic sodium retention.
EFFECTS ON RENAL FUNCTION. All diuretics may increase blood urea concentrations by increasing urea reabsorption in the medulla. Thiazides may also promote protein breakdown. In certain situations diuretics may also decrease G FR:
• Excessive diuresis may cause volume depletion and prerenal failure.
• Diuretics may cause allergic tubulo-interstitial nephritis.
• Thiazides may directly cause a drop in G FR; the mechanism is complex.

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