Practical Applications of Intravenous Fluids in Surgical Patients Shaila Shodhan Kamat
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Normal Water BalanceChapter 1

The kidneys are essential for regulating the volume and composition of body fluids. Hence key regulatory systems involving the kidneys for controlling volume, sodium and potassium concentration and the pH of body fluids should be understood thoroughly.
A most critical concept is to understand how regulation of water and sodium are integrated to defend the body against all possible disturbances in the volume and osmolality of body fluids. Simple examples of such disturbances include dehydration, blood loss, salt ingestion and plain water ingestion.
 
Water homeostasis (Fig. 1.1)
Normal day-to-day fluctuations in total body water (TBW) are small (< 0.2%) because of a fine balance between input (controlled by the thirst mechanisms) and output (controlled mainly by the kidneys), which is influenced by various hormonal factors.
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Figure 1.1: Water homeostasis
 
Distribution of total body water
Total body water (TBW)—60% of body weight in adults
  1. Two-thirds of total body water (TBW) is intracellular
  2. 2One-third of total body water (TBW) is extracellular
    1. Two-thirds of extracellular fluid is interstitial
    2. One-third of extracellular fluid is intravascular.
Age
Estimated blood volume ml/kg
Haematocrit%
Premature neonates
90
40–50
Term neonates
80
50–60
2 month – 1 year
80
30–35
1 year to adolescence
80
35–40
Adult
Male
70–75
35–40
Female
55–65
40–45
 
Regulation of total body water
The regulation of body water depends upon fine balance between intake and output orchestrated by several factors:
  1. Water intake
  2. Water output
    1. Sensible water losses
    2. Normal insensible water losses
    3. Abnormal insensible water losses.
  3. Sensors that are involved in control of water balance in the body
    1. Osmoreceptors or osmo-sodium receptors
    2. Baroreceptors
      1. Low pressure atrial baroreceptors or volume receptors
      2. High pressure aortic baroreceptors or mechanoreceptors
  4. Role of hormones in water balance
    1. Role of antidiuretic hormone (ADH) and thirst in water balance
    2. Role of renin in water balance
    3. Role of angiotensin II in water balance
    4. Role of angiotensin III in water balance
    5. Role of aldosterone in water balance
    6. Role of atrial natriuretic peptide (ANP) and B-type or brain natriuretic peptide (BNP) in water balance
    7. Role of kinins in water balance
    8. Role of dopamine in water balance
    9. Role of prostaglandin in water balance
  5. Role of the kidneys in water balance
    1. Renal filtration, reabsorption, and excretion of water
    2. Role of the kidneys in sodium excretion
    3. Physiology of urine production.
  6. Regulation of sodium concentration by regulation of water homeostasis
 
Regulation of total body water (Fig. 1.2)
3The central controller for water balance is the hypothalamus but there is no single anatomically defined ‘centre’ which is solely responsible for producing an integrated response to changes in water balance. The regulation of body water and sodium are closely inter-related.
 
I. Water Intake
Total body water content is regulated by the intake and output of water. Water intake can be considered to consist of two components: a non-regulatory component (all other fluid intake) and a regulatory component (due to thirst).
The consumption of water intake is regulated by behavioural mechanisms, including thirst and salt cravings. While almost a litre of water per day is lost through the skin, lungs and faeces, the kidneys are the major site for regulated excretion of water.
The principal sources of body water are ingested fluid, water present in the solid food and water produced as an end product of metabolism. Intravenous fluids are another common source in hospital patients.
Water intake includes ingested fluids (an adult averages 2300 ml) plus average 750 ml ingested in solid food and 300 ml generated metabolically from oxidation in food.
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Figure 1.2: Regulation of total body water
 
II. Water Output (Fig. 1.3)
4Actual and potential outlets for water are classified conventionally as sensible and insensible losses. Normal insensible losses denote losses from the skin and lungs, sensible losses denotes mainly from the kidneys and gastrointestinal tract.
Intake of water
Output for water
Sources of body water
Normal insensible losses
Sensible losses
Ingested fluid
Skin
Urine
Fluid in solid food
Metabolic water
Lung
Stool
  1. Sensible water losses
    Sensible water losses are through the kidneys and the gastrointestinal tract. Approximately 60%, i.e. about 1400 ml of the normal daily intake of water is excreted as urine, and 100 ml is present in the stool.
  2. Normal insensible water losses
    Loss of water by evaporation through the respiratory tract and diffusion through the skin is known as normal insensible water loss as it is not perceived by the individual.
    • The cholesterol-filled, cornified layer of the skin shields against a greater insensible water loss through the skin. Indeed, when the cornified layer becomes denuded, as after burn injury, the outward diffusion of water is greatly increased.
    • Insensible water losses through the skin and respiratory tract are largely mandatory but are not fixed. Normally 700 ml is lost by evaporation through the respiratory tract and 300 ml is lost through sweat by diffusion through the skin. Hence, insensible losses are approximately one litre.
    • All gases that are inhaled are saturated with water vapour at 47 mmHg. This water vapour is subsequently exhaled, accounting for an average water loss through the lungs, approximately 700 ml every 24 hours.
      zoom view
      Figure 1.3: Water output
    • 5The water content of inhaled gases decreases with temperature, which is why more endogenous water is required to achieve a water vapour pressure of 47 mmHg as environmental temperature decreases. As a result, insensible water loss from the lungs is greatest in cold weather and least in warm environments. This is consistent with the sense of dryness perceived in the respiratory passages in cold weather.
  3. Abnormal insensible water loss
    Higher amount of water is lost during fever, exercise, burns, surgery, e.g. laparotomy.
    • During laparotomy if the exposed intestine is not covered adequately with moist packs, insensible water loss is around 750 ml to 1 litre for every one hour of exposed intestine.
    • At high ambient temperatures or with significant exercising, the amount of water lost through sweating increases and reflects most of the total body water loss. Heavy exercising can lead to 50 times more water loss, through sweating, than the normal rate.
    • Increased ventilation increases the insensible loss of water through the respiratory tract. Under these conditions, renal water loss decreases to compensate for the increased sweating and insensible water loss.
 
III. Sensors that are Involved in Control of Water Balance in the Body
The main sensors that are involved in control of water balance in the body are:
  1. Osmoreceptors or osmo-sodium receptors
  2. Baroreceptors
    1. Low pressure atrial baroreceptors or volume receptors
    2. High pressure arterial baroreceptors or mechanoreceptors.
 
Role of Osmoreceptors or Osmo-sodium Receptors in Water Balance (Fig. 1.4)
The osmoreceptors are specialized cells located in the hypothalamus which respond to changes in extracellular tonicity (rather than to changes in osmolality). The critical difference between osmolality and tonicity is that all solutes contribute to osmolality but only solutes that do not cross the cell membrane contribute to tonicity.
  1. Thus, tonicity expresses the osmotic activity of solute restricted to the extracellular compartment. Tonicity is the effective osmolality and is equal to the sum of the concentrations of the solutes which have the capacity to exert an osmotic force across the membrane.6
    zoom view
    Figure 1.4: Role of osmoreceptors in water balance
  2. Osmolality takes into account the total concentration of penetrating solutes and non-penetrating solutes; whereas tonicity takes into account the total concentration of only non-penetrating solutes.
  3. As sodium accounts for 92% of extracellular fluid tonicity, these osmoreceptors (during normal physiology) function essentially as monitors of sodium in extracellular fluid. These receptors have been also called ‘osmo-sodium’ receptors.
    • Osmoreceptors are very sensitive, which respond to changes as small as a one to two per cent in tonicity.
    • Water intake can vary greatly but plasma osmolality varies only one to two per cent because of the efficient and powerful control system coupled to these osmoreceptors.
  4. These osmoreceptors are monitoring ‘water balance’ indirectly because they look at the effect of an excess or deficit of water by its effect on tonicity. This could cause a problem, if both extracellular water and solute increased together so that sodium and tonicity remained constant, e.g. an intravenous infusion of normal saline (i.e. an isotonic expansion of the extracellular fluid). Fortunately the body has several mechanisms of recognising changes in intravascular volume e .g. baroreceptors.
  5. Sodium in extracellular fluid is an effective monitor of total body water.
    • Osmoreceptors effectively respond to the change in sodium concentration in extracellular fluid. This is the factor which effectively 7controls the distribution of water between intracellular and extracellular fluid.
    • The sodium in extracellular fluid thus regulates the extracellular fluid volume and controls the ICF: ECF distribution of body water.
 
Role of Baroreceptors in Regulation of Water Balance
Baroreceptors are sensors (pressure stretch receptors) located in the blood vessels, which are less sensitive (but more potent) than the osmoreceptors. The threshold for the low pressure atrial stretch receptors to cause changes in ADH secretion is 8 to 10% change in blood volume. But when stimulated, they cause ADH levels to be increased much higher than that seem with osmoreceptors stimulation.
Hormone secretions that target the heart and blood vessels are affected by the stimulation of baroreceptors. Arterial baroreceptors convey information about arterial blood pressure, but other stretch receptors in the large veins and right atrium convey information about the low pressure parts of the circulatory system, i.e. venous blood pressure.
Baroreceptors (pressure stretch receptors) can be divided into two categories:
  • Low pressure atrial baroreceptors are present in the cardiac atria (right and left atrium) which are also called volume or cardiopulmonary receptors.
  • High pressure arterial baroreceptors which are present in the aortic arch and carotid sinus are also called mechanoreceptors.
 
Low Pressure Atrial Baroreceptors or Volume Receptors (Fig. 1.5)
  1. Low pressure stretch receptors or volume receptors are baroreceptors located in the right atrium, at the junction of the venae cavae and in the left atrium, at the junction of the pulmonary veins.
  2. Increased blood volume is detected by stretch receptors located in both atria at the veno-atrial junctions. These receptors respond to changes in the wall tension, which is proportional to the filling state of the low pressure side of circulation. It means effective intravascular volume can be independently assessed by the low pressure atrial baroreceptors.
  3. Stimulation of low pressure stretch receptors in the cardiac atria produces three effects:
    • They send inputs to osmoreceptors of hypothalamus, which in turn produces decrease in ADH, renin and aldosterone secretion. The decrease in ADH secretion results in an increase in the volume of urine excreted.
    • In addition, stretching of atrial receptors increases secretion of atrial and B-type or brain natriuretic peptide (ANP and BNP), which promotes increased water and sodium excretion through the urine.
    • Bainbridge or atrial reflex (Fig. 1.5)
      The Bainbridge reflex is also called the atrial reflex, is an increase in heart rate due to an increase in central venous pressure.8
      zoom view
      Figure 1.5: Low pressure atrial stretch receptors - Bainbridge reflex
    • As venous return increases, the pressure of the right atrium increases, which stimulates the atrial stretch receptors (low pressure receptor zones).
    • These receptors in turn signal the medullary control centres to increase the heart rate (tachycardia). Unusually, this tachycardia is mediated by increased sympathetic activity to the sino-atrial node with no fall in parasympathetic activity. This reflex is called Bainbridge reflex.
    • Increased heart rate serves to decrease the pressure in the superior and inferior ven cavae by drawing more blood out of the right atrium. This results in a decrease in atrial pressure, which serves to bring in more blood from the ven cavae, resulting in a decrease in the venous pressure of the great veins. This continues until right atrial blood pressure returns to normal levels, upon which the heart rate returns to its original level.
 
High Pressure Arterial Baroreceptors (Fig. 1.6)
High pressure arterial baroreceptors are a type of mechanoreceptors that detect the pressure of blood flowing through them, and can send messages to the central nervous system to increase or decrease total peripheral resistance and cardiac output.9
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Figure 1.6: High pressure arterial baroreceptors—Baroreceptor reflex
 
Baroreceptor Reflex (Fig. 1.6)
  1. Basically, baroreceptor reflex is initiated by stretch receptors, called either baroreceptors or pressor receptors which are located in the walls of the large systemic arteries, i.e. in the transverse aortic arch and the carotid sinuses of the left and right internal carotid arteries.
  2. The baroreceptors found within the aortic arch monitor the pressure of blood delivered to the systemic circulation, and the baroreceptors within the carotid arteries monitor the pressure of the blood being delivered to the brain.
    • A rise in pressure stretches the baroreceptors and sends input to the hypothalamus via adrenergic pathways. Aortic baroreceptors through the vagus nerve (cranial nerve X) and carotid baroreceptors through the glossopharyngeal nerve (cranial nerve IX) transmit signals into the central nervous system (the nucleus tractus solitarius in the medulla oblongata in brainstem). It stimulates vagal centre and decreases heart rate, decreases strength of contraction of myocardium and produces peripheral vasodilatation.
    • The volume receptors (low pressure baroreceptors) and the high pressure baroreceptors also send the input to the hypothalamus when there is a pressure rise.
  3. Baroreceptor reflex is the mechanism of arterial pressure control which acts immediately as a part of a negative feedback system. It is an example of a short-term blood pressure regulation mechanism. Feedback signals are then sent through the autonomic nervous system to the circulation to reduce arterial pressure towards the normal level.
  4. The Bainbridge reflex increases the heart rate and the baroreceptor reflex decreases the heart rate. They act antagonistically to control heart rate.10
    • When blood pressure increases, the baroreceptor reflex is dominant, and it decreases the heart rate.
    • When blood volume is increased, the Bainbridge reflex is dominant and it increases the heart rate. After delivery of an infant when a large volume (up to 800 ml) of uteroplacental blood is autotransfused into the mother's circulation it always results in tachycardia.
  5. Stimulation of both pressure stretch receptors (high and low) helps to decrease blood pressure with decrease in ADH and renin release and vice versa.
 
IV. Role of Hormones in Water Balance
One of the mechanisms that the body uses to control urine volume is through the action of hormones. Hormones are secreted by specialised glands in the body. The two endocrine glands that are concerned with the regulation of fluid balance within the body are the pituitary gland and the adrenal gland.
Roughly 60% of the weight of the body is water and despite wide variations in the amount of water taken each day, body water content remains incredibly stable.
Such precise control of body water and solute (sodium) concentrations is a function of several hormones acting on both the kidneys and vascular system, however there is no doubt that antidiuretic hormone (ADH) is a key player in this process. Several factors have been implicated in the control of sodium excretion but the renin-angiotensin-aldosterone system (RAAS) seems to play a key role.
 
1. Role of Antidiuretic Hormone (ADH) or Arginine Vasopressin (AVP) in Water Balance
Posterior pituitary (Fig. 1.7)
The pituitary is insignificant in appearance (about the size of a corn) but it packs an extremely powerful punch. The pituitary is actually two glands in one, posterior and anterior. Of the two, the posterior pituitary manufactures no hormones of its own, but stores two hormones that are initially secreted in a part of the brain known as the hypothalamus. These hormones are oxytocin (a hormone responsible for stimulating labour at the end of pregnancy), and antidiuretic hormone (ADH), which helps the body retain its fluids.
The posterior pituitary or neurohypophysis is an extension of the hypothalamus. It is largely a collection of axonal projections from the hypothalamus that terminate behind the anterior pituitary gland. It is composed of bundles of axons from hypothalamic neurosecretory neurones intermixed with glial cells and other poorly-defined cells called pituicytes. Roughly 100,000 axons participate in this process to form the posterior pituitary. Infundibular stalk also known as the infundibulum or pituitary stalk, bridges the hypothalamic and neurohypophysis systems.
These axons have their cell bodies in the paraventricular and supraoptic nuclei of the hypothalamus. These neurones secrete oxytocin and antidiuretic hormone classically known as posterior pituitary hormones.11
zoom view
Figure 1.7: Posterior pituitary
Formation and storage of ADH (Fig. 1.8)
Antidiuretic hormone, also commonly known as arginine vasopressin, is a nine amino acid peptide. ADH is derived from a preprohormone precursor that is synthesised in the hypothalamus.
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Figure 1.8: Formation and synthesis of ADH
12Herring bodies are dilated areas or bulges in the terminal portion of axons that contain clusters of neurosecretory granules. The granules contain oxytocin or antidiuretic hormone, along with a carrier protein called neurophysin. Both are transported slowly along the ‘hypothalamo-hypophyseal tract’ with carrier protein to the nerve endings in the posterior pituitary gland where they are stored.
The neurohypophysis contains abundant capillaries, particularly in its ventral portion where most hormone release occurs. Herring bodies often are seen in association with these capillaries. Many of these capillaries are fenestrated (contain holes), facilitating delivery of hormones into the blood.
Osmoreceptors of the hypothalamus (Fig. 1.9)
Osmoreceptors are special sensory receptors primarily found in the supraoptic and paraventricular nuclei of the hypothalamus that detect changes in extracellular osmolality. Osmoreceptors receive synaptic input from regions adjacent to the anterior wall of the third ventricle. They also receive input from ascending adrenergic pathways from the low and the high pressure baroreceptors.
ADH is released when the body is dehydrated. ADH will help the kidneys to conserve water, thus concentrating the urine and reducing urine volume.
zoom view
Figure 1.9: Osmoreceptors of the hypothalamus
13Role of osmolality, hypovolaemia and non-osmotic stimuli in ADH release
  1. Role of osmolality in ADH release (Fig. 1.10)
    • The main stimulus for secretion of ADH is increased osmolality of plasma. Reduced volume of extracellular fluid also has this effect, but its a less sensitive mechanism (note that anything that stimulates ADH secretion also stimulates thirst).
    • Plasma osmolality is closely regulated by osmoreceptors in the hypothalamus. These specialised neurones control the secretion of the antidiuretic hormone (ADH) and the thirst mechanism. Plasma osmolality is therefore, maintained within relatively narrow limits by varying both, water intake and water excretion.
      As seen in the Figure 1.11, antidiuretic hormone concentrations rise steeply and linearly with increasing plasma osmolality.
    • When plasma osmolality is below a certain threshold, the osmoreceptors are not activated and secretion of antidiuretic hormone is suppressed. When osmolality increases above the threshold, the osmoreceptors recognise this as their cue to stimulate the neurones that secrete antidiuretic hormone.
      • ADH is secreted from the posterior pituitary gland in response to reductions in plasma volume and in response to increase in the plasma osmolality due to shrinkage of osmoreceptors.
        zoom view
        Figure 1.10: Role of osmolality in ADH release
        14
        zoom view
        Figure 1.11: ADH concentrations and plasma osmolality
      • Conversely, a decrease in extracellular osmolality and increase in plasma volume causes osmoreceptors to swell and suppresses the release of ADH.
      • Feedback control: Increased ADH release in response to increased plasma osmolality allows reabsorption of water in the kidneys. This reduces plasma solute, i.e. sodium, which is detected by the osmoreceptors in the hypothalamus, allows sensitive feedback control of ADH secretion. Decreased ADH release allows a water diuresis, which tends to increase osmolality to normal.
        In response to changing plasma sodium, release of ADH changes, which can vary urine osmolality from 50 to 1200 mOsmol/kg and urinary volume from 0.4 to 20 L/day.
  2. Role of hypovolaemia in ADH release (Fig. 1.12)
    • Hypovolaemia is a more potent stimulus for ADH release than hyperosmolality. A hypovolaemic stimulus to ADH secretion will override a hypotonic inhibition and volume will be conserved at the expense of tonicity.
    • The maximum levels of ADH reached with significant volume depletion (20%) are about 40 pg/ml which is larger than the 12-15 pg/ml reached with a maximum isovolaemic increase in osmolality.
    • Secretion of antidiuretic hormone is also stimulated by decrease in blood pressure, conditions sensed by stretch receptors in the heart, large arteries and veins. Changes in blood pressure are not as sensitive stimulator as increased osmolality. Loss of 15 or 20% of blood volume by haemorrhage results in massive secretion of antidiuretic hormone.15
      zoom view
      Figure 1.12: Role of hypovolaemia in ADH release
    • Angiotensin II stimulates ADH secretion, in keeping with its general pressor and pro-volaemic effects on the body.
    • Atrial and B-type natriuretic peptide inhibits ADH secretion, by inhibiting Angiotensin II-induced stimulation of ADH secretion.
  3. Non-osmotic stimulus for release of antidiuretic hormone
    • Secretion of ADH is stimulated by pain, nausea, emotional stress, hypoxia and drugs such as morphine and barbiturates.
    • ADH is released by the posterior pituitary gland in response to positive pressure ventilation and surgical stimuli.
Role of ADH in pregnant patients
Osmoreceptors monitor the solute concentrations in the blood. When the osmoreceptors send excitatory messages to the “ADH secreting neurones”, less urine is produced, leaving more volume in the circulating blood. During pregnancy the osmoreceptors are “reset” to deal with the increased blood volume of pregnancy.
  1. The actions of the hormones of the posterior pituitary are important in the pregnant woman who is at risk for preterm labour especially if there is maternal dehydration.
  2. 16Maternal dehydration may trigger the secretion of ADH by the posterior pituitary. It is thought that oxytocin may also be released at the same time, bringing about uterine contraction before the optimum time. These uterine contractions, or uterine “irritability” (low intensity, high frequency contractions) of preterm labour are often treated with maternal hydration.
  3. Women at risk for preterm labour are encouraged to drink abundant amounts of water throughout the day, and, if hospitalised for contractions, hydration with a bolus of intravenous fluid is often effective to “quiet” the uterus.
Role of ADH in trauma patients
In trauma patients, a great deal of ADH is released, to counteract blood loss. The result is constriction of smooth muscles of the blood vessels, in order to raise the arterial blood pressure. Very little blood is getting to the baby through the constricted blood vessels if patient is pregnant.
Physiological Effects of Antidiuretic Hormone
Effects of ADH on the Kidney (Fig. 1.13)
The single most important effect of antidiuretic hormone is to conserve body water by reducing the loss of water in urine. ADH initiates its physiological actions by combining with specific receptors of ADH (vasopressin receptors), i.e. V1 and V2 receptors.
  1. Antidiuretic hormone binds to the V2 receptors on cells in the distal renal tubules and collecting ducts of the kidney, which stimulates insertion of “water channels” or aquaporins 2 into the membranes of cells.
    zoom view
    Figure 1.13: Effects of ADH on the kidney
  2. 17Insertion of aquaporin-2 channels requires signalling by the antidiuretic hormone. These channels transport solute-free water through tubular cells. This allows water reabsorption and excretion of more concentrated urine, i.e. antidiuresis. It leads to a decrease in plasma osmolality and an increase osmolality of urine.
  3. Without ADH, little water is reabsorbed in the collecting ducts and dilute urine is excreted.
Effects of ADH on the Vascular System
Though the most important role of ADH is to regulate water in the body, in many species, high concentrations of antidiuretic hormone causes widespread constriction of arterioles, which leads to increased arterial pressure. It was for this effect that the name vasopressin was coined. In healthy humans, antidiuretic hormone has minimal pressor effects.
  1. The V1 receptors are located on blood vessels and are responsible for the vasopressor action by ADH. ADH increases peripheral vascular resistance (vasoconstriction) and thus increases arterial blood pressure.
  2. This effect appears small in healthy individuals; however it becomes an important compensatory mechanism for restoring blood pressure in hypovolaemic shock which occurs during haemorrhage.
  3. However, this response appears to be reset within 32 hours of sustained hypovolaemia.
Role of thirst in water balance
There is an interesting parallel between antidiuretic hormone secretion and thirst. Both phenomena appear to be stimulated by hypothalamic osmoreceptors, although probably not the same ones. The osmotic threshold for antidiuretic hormone secretion is considerably lower than for thirst, as if the hypothalamus is saying “Let's not bother him by invoking thirst unless the situation is bad enough that antidiuretic hormone cannot handle it alone.”
  1. Thirst is the primary mechanism of controlling water intake, is triggered by an increase in body fluid osmolality or by a decrease in extracellular volume (in response to a decrease in volume of the plasma).
  2. Thirst leads to drinking which is a powerful defense against serum hyperosmolality. Drinking stimulates mechanoreceptors in the mouth and pharynx. These peripheral receptors provide input to the hypothalamus and the sensation of thirst is attenuated. This occurs even before any reduction in plasma tonicity. This may safeguard against the over-ingestion of water as there is an inevitable delay before the ingested water is absorbed and available to decrease plasma osmolality.
  3. As long as access to water is unrestricted and the person is able to drink, then significant serum hyperosmolality will not develop. For example, elderly patients with non-ketotic hyperglycaemia do not become significantly hyperosmolar unless water intake becomes restricted for some reason.
18 Factors influencing thirst mechanism (Fig. 1.14)
Both the thirst and the ADH mechanisms are regulated in the hypothalamus. The thirst centre is located in the lateral hypothalamus.
  1. Activation of osmoreceptors in the lateral pre-optic area of the hypothalamus by increase in extracellular osmolality stimulates thirst centre and causes the individual to consume water. Conversely, hypo-osmolality suppresses the thirst centre.
  2. Thirst is the major defense mechanism against hyperosmolality and hypernatraemia, because it is the only mechanism that increases water intake. Unfortunately, the thirst mechanism is only operative in conscious individuals who are capable of drinking.
    Stimulation of Thirst and ADH Secretion
    Osmotic
    ECF hyperosmolality
    Non-osmotic
    Hypotension
    Aortic, carotid and atrial baroreceptors
    Pain
    Emotional stress
    Hyperthermia
    Drugs
    Opiates
    Anaesthetics
    β agonists
    Cholinergic agents
    Chlorpropamide
    Renin-angiotensin stimulation
    zoom view
    Figure 1.14: Factors influencing thirst mechanism
  3. 19The threshold of thirst for osmotic stimuli has a higher set-point then that for ADH release. Some consider thirst as the ‘back up’ mechanism that acts only when the ADH release is insufficient to reduce the plasma osmolality to normal.
The four major stimuli to thirst are:
  1. Hypertonicity
    Cellular dehydration acts via an osmoreceptor mechanism in the hypothalamus.
  2. Hypovolaemia
    Low volume is sensed via the low pressure baroreceptors in the great veins and right atrium.
  3. Hypotension
    The high pressure baroreceptors in carotid sinus and aorta provide the sensors for this input.
  4. Angiotensin II
    This is produced consequent to the release of renin by the kidney in response to renal hypoperfusion.
 
2. Role of Renin in Water Balance
Renin is also known as an angiotensinogenase. It is an enzyme that participates in the body's renin-angiotensin system (RAS) is also known as the renin-angiotensin-aldosterone axis which regulates extracellular volume, and arterial vasoconstriction. Thus, it regulates the body's mean arterial blood pressure.
The capillary vascular supply of nephron consists of two distinct capillary beds, the glomerular capillary bed and the peritubular capillary bed. A vessel leading to and from the glomerulus is the glomerular capillary bed. The afferent arteriole feeds the bed while the efferent arteriole drains it. The glomerular capillary bed has no comparison elsewhere in the body.
Glomerular capillary bed is a high-pressure bed along its entire length. Its high pressure is a result of two major factors:
  1. The bed is fed and drained by arterioles (arterioles are high-resistance vessels as opposed to venules, which are low-resistance vessels).
  2. The afferent feeder arteriole is larger in diameter than the efferent arteriole draining the bed.
The high hydrostatic pressure created by these two anatomical features forces out fluid and blood components smaller than proteins from the glomerulus into the glomerular or Bowman's capsule. That is, it forms the filtrate which is processed by the nephron tubule.
  1. Juxtaglomerular (JG) cells are associated with the afferent arteriole while entering the renal glomeruli. They are the primary site of renin storage and release in the body (Fig. 1.15).20
    zoom view
    Figure 1.15: Nephron with juxtaglomerular apparatus (For color version, see Plate 1)
    zoom view
    Figure 1.16: Juxtaglomerular apparatus
  2. In the kidney, the macula densa is an area of closely packed specialised cells lining the wall of the distal tubule, and it lies adjacent to the juxtaglomerular cells of the afferent arteriole. The cells of the macula densa are chemoreceptors that sense the tubular concentration of sodium and can help to regulate volume status. Macula densa region with juxtaglomerular cells of the kidney is called juxtaglomerular apparatus, which is another modulator of blood osmolality (Fig. 1.16).
21 Factors influencing release of renin (Fig. 1.17)
Renin is a proteolytic enzyme that is released into the circulation primarily from juxtaglomerular cells of kidney, which is activated via signalling from the macula densa. Its release is stimulated by:
  1. Increased activity of renal sympathetic nerves
    Beta1 adrenoceptors located on the juxtaglomerular cells respond to renal sympathetic nerve stimulation by releasing renin. Increased activity of renal sympathetic nerve is seen when plasma volume decreases.
  2. Renal artery hypotension
    Renal artery hypotension is caused by systemic hypotension or renal artery stenosis. A reduction in afferent arteriolar pressure causes the release of renin from the juxtaglomerular cells, whereas increased afferent arteriolar pressure inhibits renin release.
  3. Decreased glomerular filtration
    When afferent arteriolar pressure is reduced, glomerular filtration decreases, and this reduces sodium and chloride in the distal tubule. A decrease in sodium and chloride concentration in distal tubule is sensed by macula densa that has following effects:
    • It increases renin release from the juxtaglomerular cells which are the major storage sites for renin.
      zoom view
      Figure 1.17: Factors influencing release of renin
    • 22Decrease filtration fraction serves as an important mechanism contributing to the release of renin when there is afferent arteriole hypotension.
    • Renin's primary function is therefore eventually to cause an increase in blood pressure, leading to restoration of perfusion pressure in the kidneys.
    When sodium and chloride is elevated in the tubular fluid, renin release is inhibited. Hyperkalaemia also releases renin. There is evidence that prostaglandins (PGE2 and PGI2) stimulate renin release in response to reduced sodium and chloride in the distal tubule.
Role of renin in water balance
Angiotensinogen is a glycoprotein synthesised and secreted into the bloodstream by the liver. Renin acts on angiotensinogen (gamma globulin from the liver) and converts it into angiotensin I. Angiotensin I plays role in water balance through angiotensin II and aldosterone.
Renin indirectly increases sodium reabsorption, and increase in blood volume and/or pressure, due to formation of angiotensin II and release of aldosterone.
 
3. Role of Angiotensin II in Water Balance (Fig. 1.18)
Angiotensin converting enzyme (ACE) is also known as kinase III is widely-distributed in the small vessels of the body, but particularly concentrated in the pulmonary capillaries of the lungs. Angiotensin converting enzyme (ACE) converts angiotensin I to its active form angiotensin II (vasoconstrictor) and inactivates bradykinin (vasodilator).
zoom view
Figure 1.18: Role of Angiotensin II in water balance Patterned arrows shows action of angiotensin II
  1. 23Angiotensin II is a potent constrictor of all blood vessels.
    It acts on the smooth muscle and, therefore, raises the peripheral resistance, posed by these arteries to the heart. The heart, trying to overcome this increase in its ‘load’, by working more vigorously, causing the blood pressure to rise and restore blood pressure.
  2. Angiotensin II conserves blood volume, by reducing urinary loss through the secretion of vasopressin (ADH) from the posterior pituitary gland.
  3. Stimulates cardiac hypertrophy and vascular hypertrophy.
  4. The RAAS also acts on the CNS to increase water intake by stimulating thirst.
  5. Facilitates norepinephrine release from sympathetic nerve endings and inhibits norepinephrine re-uptake by nerve endings, thereby enhancing sympathetic adrenergic function.
  6. Angiotensin II is converted to angiotensin III. Angiotensin III acts on the adrenal glands and releases aldosterone.
 
4. Role of Angiotensin III in Water Balance
Angiotensin III stimulates aldosterone production without vasoconstriction.
 
5. Role of Aldosterone in Water Balance
So far we have discussed the role of the pituitary gland (through the release of ADH) and thirst in the regulation of body fluids. These are the two primary mechanisms that are responsible for making sure that there is an appropriate water and sodium level in the blood.
The second set of glands that participate in the regulation of body fluids are the adrenal glands. The adrenals sit on top of each kidney like a cap and, although they usually vary somewhat in size and shape, they generally look like pyramids. Like the pituitary, each adrenal gland is really two glands in one. The central portion is termed the adrenal medulla, and the outer part is the adrenal cortex. The two sections represent distinct glands that secrete different hormones.
All the hormones secreted by the adrenal cortex are “adrenocorticosteroids.” There are three groups of adrenocorticosteroids, each secreted by cells in a different layer of the cortex:
  1. Glucocorticoids, which influence the metabolism of carbohydrates, proteins, and fats.
  2. Sex hormones, which affect sexual characteristics.
  3. Mineralocorticoids, which helps to regulate the concentrations of extracellular electrolytes, e.g. aldosterone.
24Aldosterone secretion is controlled in various ways:
  1. Increased potassium levels or decreased sodium content are the most sensitive stimulators of aldosterone.
  2. The adrenal cortex also directly senses change in plasma osmolality. When the osmolality increases above normal and aldosterone secretion is stimulated.
  3. The stretch receptors located in the atria of the heart detect decreased blood pressure. The stimulated stretch receptors send impulses to the adrenal gland to release aldosterone.
Mechanism of action of aldosterone (Figs 1.19 and 1.20)
Angiotensin III acts on the adrenal glands and releases aldosterone. Aldosterone is a yellow steroid hormone (mineralocorticoid family) produced by the outer-section (zona glomerulosa) of the adrenal cortex in the adrenal gland.
Aldosterone acts primarily on the distal tubules and collecting ducts of the kidneys. Aldosterone increases permeability of sodium channel, potassium channel and activity of sodium potassium pump.
This hormone acts mainly through the kidneys to maintain the homeostasis of sodium and potassium ions. It causes the kidney to excrete potassium (K+) and to reabsorb sodium back into the bloodstream. More specifically, aldosterone causes the kidneys to conserve sodium ions (Na+) and to excrete potassium ions (K+). At the same time, it promotes water conservation and reduces urine output.
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Figure 1.19: Mechanism of action of aldosteroneNote: Large Na+, K+ shows high concentration and vice versa
25
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Figure 1.20: Role of aldosterone in water balance
  1. The mechanism that controls the secretion of aldosterone is primarily responsive to the potassium ion (K+) concentration in body fluids. This mechanism operates as a negative feedback loop to detect high levels of K+ and to release aldosterone so that the K+ level can be reduced. Or, if the K+ level is too low, less aldosterone will be released so that K+ is allowed to accumulate.
    • As the K+ concentration rises, sensors in the body detect this increase and signal the adrenal cortex to release more aldosterone into the bloodstream.
    • The blood carries aldosterone to the kidneys which, in turn, stop reabsorbing the K+ back into the bloodstream, causing more K+ to be excreted in the urine.
  2. Aldosterone secretion is also stimulated in response to changes in the sodium on (Na+) concentration in the blood. In this case, if low levels of Na+ are detected by the body, the adrenal cortex is stimulated to release aldosterone.
    • The presence of aldosterone stimulates the tubules to reabsorb sodium salts back into the blood at a faster rate so that it can remain in the body.
    • On the other hand, if high levels of Na+ are detected by the body, the adrenal cortex holds back on the release of aldosterone to decrease reabsorption of the salt back into the blood, allowing more to be excreted.
  3. 26Finally, the presence of aldosterone tends to increase tubular water reabsorption (that is, water tends to flow out of the kidney tubules back into the blood).
  4. Aldosterone is a part of the renin-angiotensin system. Aldosterone is the final common pathway in a complex response to decreased effective arterial volume, i.e. hypovolaemia.
The term “salt-and water-retaining hormone,” therefore, is a descriptive nickname for aldosterone. Aldosterone can also be called the “potassium-eliminating hormone”.
Summary (Figs 1.21 and 1.22)
The net effect of aldosterone on urine excretion is a decrease in the amount of urine excreted, with an increase in the osmolality of the urine. The lack of aldosterone causes less sodium to be reabsorbed in the distal tubule. The overall effect of aldosterone is to increase reabsorption of sodium and water in the kidney, expanding of intravascular fluid volume and, therefore, increasing blood pressure.
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Figure 1.21: Renin-angiotensin-aldosterone system (For color version, see Plate 1)
27
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Figure 1.22: Summary
 
6. Role of Atrial Natriuretic Peptide (ANP) and B-type Brain Natriuretic Peptide (BNP) in Water Balance (Fig. 1.23)
Two powerful hormonal systems regulate total body sodium. The renin-angiotensin-aldosterone pathway is regulated not only by the mechanisms that stimulate renin release, but it is also modulated by natriuretic peptides (ANP and BNP) released by the heart. These natriuretic peptides act as an important counter-regulatory system.
The natriuretic peptide defends against sodium overload and the reninangiotensin-aldosterone can defend against sodium depletion and hypovolaemia.
  1. Atrial natriuretic peptide (ANP) is a polypeptide hormone involved in the homeostatic control of body water and sodium. ANP is released from the cardiac atria in response to increased atrial stretch.
  2. Brain natriuretic peptide, now known as B-type natriuretic peptide (BNP) secreted by the ventricles of the heart in response to excessive stretching of heart muscle cells (cardiomyocytes). Brain natriuretic peptide is named as such because it was originally identified in extracts of porcine brain, although in humans it is produced mainly in the cardiac ventricles.
Physiological action of ANP and BNP
ANP and BNP are released due to the increased atrial and ventricles stretch due to expanded extracellular volume and in response to high blood pressure. Both exerts vasodilator effects and increases renal excretion of water and sodium.
ANP and BNP dilate the afferent glomerular arteriole, constrict the efferent glomerular arteriole, and relax the mesangial cells. This increases pressure in the glomerular capillaries, thus increasing the glomerular filtration rate (GFR), resulting in greater excretion of sodium and water.28
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Figure 1.23: Role of ANP and BNP in water balance
ANP and BNP inhibit renin secretion, thereby inhibiting the reninangiotensin system. It also reduces aldosterone secretion by the adrenal cortex since angiotensin III formation is reduced. Reduced aldosterone decreases sodium reabsorption in the distal convoluted tubule and cortical collecting duct of the nephron. ANP and BNP antagonises vasoconstriction secondary to angiotensin II.
ANP and BNP are the predominant salt excreting hormone resulting in decreased sodium reabsorption producing dilute urine (300 mOsm/kg) and abundant urine sodium (80 mEq/L).
The physiological actions of BNP are similar to ANP and include decrease in systemic vascular resistance and central venous pressure as well as an increase in natriuresis. Thus, the net effect of BNP and ANP is a decrease in blood volume which lowers systemic blood pressure and afterload, yielding an increase in cardiac output, partly due to a higher ejection fraction. ANP and BNP secretion is decreased during hypovolaemia.
Therapeutic manipulation of this pathway is very important in treating hypertension and heart failure. ACE inhibitors, angiotensin II receptor blockers and aldosterone receptor blockers are used to decrease arterial pressure, ventricular afterload, blood volume and hence ventricular preload, as well as to inhibit and reverse cardiac and vascular hypertrophy.29
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Figure 1.24: Role of dopamine in water balance
 
7. Role of Kinins in Water Balance
Kinins are converted from kininogens by kallikrein and are regulated by salt intake, renin release and hormone levels. They cause renal vasodilatation and natriuresis.
 
8. Role of Dopamine in Water Balance (Fig. 1.24)
Dopamine is produced in the kidneys following conversion from L-dopa under the action of the L-amino acid decarboxylase enzyme, present in the proximal tubules.
The conversion is controlled by a high salt diet, leading to increased urinary sodium loss, as dopamine inhibits sodium reabsorption in the proximal tubule and contributes to the increase in urine output. This is seen following the administration of a low dose of dopamine.
 
9. Role of Prostaglandins in Water Balance (Fig. 1.25)
The renal synthesis of prostaglandins, such as prostaglandin E2 (PGE2) and prostaglandin I2 (PGI2), tends to maintain renal blood flow and GFR through vasodilatation and directly increases water and sodium excretion.
Dopaminergic renal vasodilatation in part acts through the release of PGI2. This is because administration of dopaminergic antagonists leads to reduced urinary prostaglandins and loss of dopaminergic vasodilatation.
Thereby, explaining why a low dose of dopamine appears to be ineffective in septic ICU patients who already have a prostaglandin-driven kidney.30
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Figure 1.25: Role of prostaglandins in water balance
 
V. Role of the Kidneys in Water Balance (Fig. 1.26)
Urine is produced not only in order to eliminate many of the cellular waste products, but also to control both the amount and the composition of the extracellular fluid in the body. Controlling the amount of water and chemicals in the body is essential to life, and our body does so by producing various amounts of urine so that we can either excrete the “extra” water and chemicals (mainly sodium) or conserve the water and chemicals when they are in short supply.
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Figure 1.26: Urinary excretion of water
31Therefore, the volume of urine that we excrete everyday is a reflection of how much extracellular fluid and sodium our bodily have to spare. The kidney tubule regulation of the salt and water in our bodies is the most important factor in determining urine volume. Too much water and salt in our bodies is dangerous and too little water and salt in our bodies is also dangerous. Therefore, the level of water and salts excreted in urine and the urine volume is adjusted to the needs of the body. As a general rule, however, and under optimum conditions, the body produces urine at a rate of about 1 ml/min.
In other words kidneys are the major regulators of water output. The kidneys can directly control the volume of body fluids, is by the amount of water excreted in the urine. Regulation of water balance by the kidneys is dependent on its ability to excrete urine with an osmolality that varies from maximal dilution to maximal concentration.
  1. Either the kidneys can conserve water by producing urine that is concentrated relative to plasma, or they can rid the body of excess water by producing urine that is dilute relative to plasma.
  2. ADH provides a mechanism for adjusting water output via the kidney.
  3. Reabsorption of filtered water and sodium is enhanced by hormonal factors such as antidiuretic hormone (ADH) and renin-angiotensin-aldosterone system and decreased by atrial and B-type natriuretic peptide (ANP and BNP).
Renal water handling has three important components (Fig. 1.27):
  1. Delivery of tubular fluid to the diluting segments of the nephron
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    Figure 1.27: Renal filtration, reabsorption, and excretion of water. The black arrows represent electrolytes and the patterned arrows represent water. Water and electrolytes are filtered by the glomerulus
    The numbers (300, 600, 900 and 1200) between the descending and ascending loops of Henle represent the osmolality of the interstitium in mOsm/kg.
  2. 32Separation of solute and water in the segments
  3. Variable reabsorption of water in the collecting ducts.
Proximal Tubule (1)
In the proximal tubule, water and electrolytes are reabsorbed isotonically.
Descending and Ascending Loop of Henle (2)
  • In the descending loop of Henle, water is absorbed to achieve osmotic equilibrium with the interstitium while electrolytes are retained.
  • This concentrated fluid is diluted by the active reabsorption of electrolytes in the ascending loop of Henle and in the distal tubule, both of which are relatively impermeable to water.
    • The cells of the macula densa of distal tubule are chemoreceptors that sense the tubular concentration of sodium and can helps to regulate volume status.
Medullary (3a) and Cortical (3b) Diluting Sites
  • The delivery of solute and fluid to the distal nephron is a function of proximal tubular reabsorption, as proximal tubular reabsorption increases, delivery of solute to the medullary (3a) and cortical (3b) diluting sites decreases.
  • In the diluting sites, electrolyte free water is generated through selective reabsorption of electrolytes while water is retained in the tubular lumen, generating a dilute tubular fluid.
Collecting ducts (in the absence of vasopressin—ADH) (4a) and collecting ducts (in the presence of vasopressin)(4b)
As fluid in the distal tubule enters the collecting duct, osmolality is approximately 50 mOsm/kg.
  • In the absence of vasopressin (ADH), the collecting ducts (4a) remain relatively impermeable to water and dilute urine is excreted.
  • When vasopressin (ADH) acts on the collecting ducts (4b), water is reabsorbed since the collecting duct becomes vasopressin responsive nephron segments, allowing the excretion of concentrated urine.
Role of the kidneys in sodium reabsorption (Fig. 1.28)
More than 99% of the filtered sodium is reabsorbed by the kidneys at four sites.
  1. Proximal Tubule (1)
    50-70%, absorption is active iso-osmotic (having the same osmotic pressure or exhibiting equal osmotic pressure) reabsorption. (Isotonic is when a solution has the same salt concentration as the blood and cells of the human body).
  2. Ascending Loop of Henle (2)
    10-20%, absorption is secondary to active reabsorption of chloride.
  3. Distal Tubule (3)
    10% is active reabsorption under influence of aldosterone. Bulk reabsorption occurs at the proximal tubule but the eventual sodium concentration of the urine is dependent upon distal tubular nephron.33
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    Figure 1.28: Role of the kidneys in sodium reabsorption
  4. Collecting duct 1% (4)
    1% absorption is active absorption.
Hormonal control of urine production (Fig. 1.29)
  1. Atrial and B-type natriuretic peptide (ANP and BNP) is released from the heart when extracellular volume is increased.
    • ANP and BNP increases glomerular filtration rate (GFR) by increasing blood pressure and the filtration fraction.
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      Figure 1.29: Hormonal control of urine production
      34
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      Figure 1.30: Regulation of sodium concentration by regulation of water homeostasis
      35
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      Figure 1.31: Regulation of sodium concentration by regulation of water homeostasis—Summary
    • Urine production is increased by ANP and BNP since it inhibits sodium reabsorption in the distal nephron.
  2. Urine production is reduced by the antidiuretic hormone (ADH), which works on the collecting duct.
 
VI. Regulation of Sodium Concentration by Regulation of Water Homeostasis—Summary (Figs 1.30 and 1.31)
Osmolality sensors (osmoreceptors) are neurones located in the hypothalamus, which stimulate thirst and antidiuretic hormone release (vasopressin) from posterior pituitary in the circulation. The osmoreceptors are by far more sensitive, enabling fine control over plasma volume. Strong release of ADH occurs in response to reduced plasma volume, irrespective of the tonicity of plasma.
ADH is stored as granules in the posterior pituitary and is released in response to an increase in serum osmolality. Under normal conditions, serum osmolality and therefore sodium concentration (which is predominant ion in ECF) is regulated by water homeostasis (Figs 1.32 and 1.33).
Water balance naturally fluctuates with the dictates of sodium balance (renin –angiotensin system). The urine sodium content can be used to differentiate oliguric states. Normal responses to hypovolaemia make urine sodium content low (<20 mmol/L) whereas in acute tubular necrosis it usually exceeds 40 mmol/L. Water losses which are sufficient to cause ECF volume contraction, hypotension, and decrease in cardiac output stimulate ADH release, causing water retention and dilutional hyponatraemia.36
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Figure 1.32: Role of sodium in ADH release
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Figure 1.33: Summary of water homeostasis
37Sodium and water metabolism are intimately related, although controlled by separate mechanisms. The movement of sodium is always accompanied by water to maintain osmotic equilibrium. Thus, in conditions of sodium depletion or accumulation, there is always an associated shift of water, which is the basis to understand intravenous fluid infusion in various circumstances.