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SGD 23: FLUID-ELECTROLYTES

1.Sam, a 35 year old male underwent transphenoidal surgery. For a pituitary macroadenoma. Post-operatively, urine
volume is 18L/day, serum Na is 155 mEq/L, and urine osmolality is 50mOsm/kg H20. On PE, he has dry mouth and lips. He
is started on 0.9% NaCl solution as IV fluid(IVF).

a) What’s the effect of giving the above mentioned IVF? Is it the right choice for Sam’s condition
Normal values:
Urine vol. : 800-2000mL/day
Serum Na: 135-145 mEq/L
Urine osmolality: 500 to 800mOsm/kg H20

Patient Values:
Urine vol. : 18L/day
Serum Na: 155 mEq/L
Urine osmolality: 50 mOsm/kg H20

Comparing the patient values to the normal values, serum Na of patient is above the nornal range thus it can be
considered hypertonic. In this case, the 0.9%NaCl solution IV fluid, which is normally isotonic to normal serum Na levels
will now be hypotonic to the patient's blood. Theoretically, adding a hypotonic solution to a red cell solution would cause
the cells to swell and burst resulting to hemolysis. Considering this, 0.9%NaCl may not be the right choice choice. An IV
fluid with a higher NaCl concentration should be considered.

b.) Fig 34-1

Osmotic Control of ADH Secretion


Changes in the osmolality of body fluids play the most important role in regulating secretion of ADH; changes as minor
as 1% are sufficient to alter it significantly. Although neurons in the supraoptic and paraventricular nuclei respond to
changes in body fluid osmolality by altering their secretion of ADH, it is clear that there are separate cells in the
anterior hypothalamus that are exquisitely sensitive to changes in body fluid osmolality and therefore play an important
role in
regulating the secretion of ADH.* These cells, termed osmoreceptors, appear to behave as osmometers and sense
changes in body fluid osmolality by either shrinking or swelling. The osmoreceptors respond only to solutes in plasma
that are effective osmoles
(see Chapter 1). For example, urea is an ineffective osmole when the function of osmoreceptors is considered. Thus,
elevation of the plasma urea concentration alone has little effect on ADH secretion. When the effective osmolality of
plasma increases, the osmoreceptors send signals to ADH-synthesizing/ secreting cells located in the supraoptic and
paraventricular nuclei of the hypothalamus, and synthesis and secretion of ADH are stimulated. Conversely, when the
effective osmolality of plasma is reduced, secretion is inhibited. Because ADH is rapidly degraded in plasma, circulating
levels can be reduced to zero within minutes after secretion is inhibited. As a result, the ADH system can respond
rapidly to fluctuations in body fluid osmolality. Figure 34-2, A, illustrates the effect of changes in plasma osmolality on
circulating ADH levels. The slope
of the relationship is quite steep and accounts for the sensitivity of this system. The set point of the system is the
plasma osmolality value at which ADH secretion begins to increase. Below this set point, virtually no ADH is released.
The set point varies among individuals and is genetically determined. In healthy adults, it varies from 275 to 290
mOsm/kg H2 O (average, ≈ 280 to 285 mOsm/kg H2 O). Several physiological factors can also change the set point in a
given individual. As discussed later, alterations in blood volume and pressure can shift it. In addition, pregnancy is
associated with a decrease in the set point.

Increase osmolality -> osmoreceptors are stimulated -> activation of ADH-secreting cells to synthesize and release ADH
-> nerve impulses liberate ADH from axon terminals to posterior pituitary -> enter bloodstream -> retention of water ->
decrease urine output -> decrease water loss from sweat glands

Hemodynamic Control of ADH Secretion


A decrease in blood volume or pressure also stimulates secretion of ADH. The receptors responsible for this response
are located in both the low-pressure (left atrium and large pulmonary vessels) and the high pressure (aortic arch and
carotid sinus) sides of the circulatory system. Because the low-pressure receptors are located in the high-compliance
side of the circulatory system (i.e., venous) and because the majority of blood is in the venous side of the circulatory
system, these low-pressure receptors can be viewed as responding to overall vascular volume. The high-pressure
receptors respond to arterial pressure. Both groups of receptors are sensitive to stretch of the wall of the structure in
which they are located (e.g., cardiac atrial wall, wall of the aortic arch) and are termed baroreceptors. Signals from
these receptors are carried in afferent fibers of the vagus and glossopharyngeal nerves to the brainstem (solitary tract
nucleus of the medulla oblongata), which is part of the center that regulates heart rate and blood pressure (see also
Chapter 18). Signals are then relayed from the brainstem to the ADH-secreting cells of the supraoptic and
paraventricular hypothalamic nuclei. The sensitivity of the baroreceptor system is less than that of the osmoreceptors,
and a 5% to 10% decrease in blood volume or pressure is required before ADH secretion is stimulated. This is illustrated
in Figure 34-2, B. A number of substances have been shown to alter the secretion of ADH through their effects on
blood pressure, including bradykinin and histamine, which lower pressure and thus stimulate ADH secretion, and
norepinephrine, which increases blood pressure and inhibits ADH secretion. The sensitivity of the baroreceptor system
is less than that of the osmoreceptors, and a 5% to 10% decrease in blood volume or pressure is required before ADH
secretion is stimulated. This is illustrated in Figure 34-2, B. A number of substances have been shown to alter the
secretion of ADH through their effects on blood pressure, including bradykinin and histamine, which lower pressure and
thus stimulate ADH secretion, and norepinephrine, which increases blood pressure and inhibits ADH secretion.

5-10% Decrease in blood volume/pressure -> baroreceptors are stimulated -> signals sent by afferent fibers of vagus
and glossopharyngeal nerves to the brainstem -> activation of ADH-secreting cells to synthesize and release ADH ->
nerve impulses liberate ADH from axon terminals to posterior pituitary -> enter bloodstream -> retention of water ->
decrease urine output -> decrease water loss
c.)
Osmotic Control of ADH Secretion
Changes in the osmolality of body fluids play the most important role in regulating secretion of ADH; changes as minor
as 1% are sufficient to alter it significantly. Although neurons in the supraoptic and paraventricular nuclei respond to
changes in body fluid osmolality by altering their secretion of ADH, it is clear that there are separate cells in the
anterior hypothalamus that are exquisitely sensitive to changes in body fluid osmolality and therefore play an important
role in
regulating the secretion of ADH.* These cells, termed osmoreceptors, appear to behave as osmometers and sense
changes in body fluid osmolality by either shrinking or swelling. The osmoreceptors respond only to solutes in plasma
that are effective osmoles
(see Chapter 1). For example, urea is an ineffective osmole when the function of osmoreceptors is considered. Thus,
elevation of the plasma urea concentration alone has little effect on ADH secretion. When the effective osmolality of
plasma increases, the osmoreceptors send signals to ADH-synthesizing/ secreting cells located in the supraoptic and
paraventricular nuclei of the hypothalamus, and synthesis and secretion of ADH are stimulated. Conversely, when the
effective osmolality of plasma is reduced, secretion is inhibited. Because ADH is rapidly degraded in plasma, circulating
levels can be reduced to zero within minutes after secretion is inhibited. As a result, the ADH system can respond
rapidly to fluctuations in body fluid osmolality. Figure 34-2, A, illustrates the effect of changes in plasma osmolality on
circulating ADH levels. The slope
of the relationship is quite steep and accounts for the sensitivity of this system. The set point of the system is the
plasma osmolality value at which ADH secretion begins to increase. Below this set point, virtually no ADH is released.
The set point varies among individuals and is genetically determined. In healthy adults, it varies from 275 to 290
mOsm/kg H2 O (average, ≈ 280 to 285 mOsm/kg H2 O). Several physiological factors can also change the set point in a
given individual. As discussed later, alterations in blood volume and pressure can shift it. In addition, pregnancy is
associated with a decrease in the set point.

Increase osmolality -> osmoreceptors are stimulated -> activation of ADH-secreting cells to synthesize and release ADH
-> nerve impulses liberate ADH from axon terminals to posterior pituitary -> enter bloodstream -> retention of water ->
decrease urine output -> decrease water loss from sweat glands

Hemodynamic Control of ADH Secretion


A decrease in blood volume or pressure also stimulates secretion of ADH. The receptors responsible for this response
are located in both the low-pressure (left atrium and large pulmonary vessels) and the high pressure (aortic arch and
carotid sinus) sides of the circulatory system. Because the low-pressure receptors are located in the high-compliance
side of the circulatory system (i.e., venous) and because the majority of blood is in the venous side of the circulatory
system, these low-pressure receptors can be viewed as responding to overall vascular volume. The high-pressure
receptors respond to arterial pressure. Both groups of receptors are sensitive to stretch of the wall of the structure in
which they are located (e.g., cardiac atrial wall, wall of the aortic arch) and are termed baroreceptors. Signals from
these receptors are carried in afferent fibers of the vagus and glossopharyngeal nerves to the brainstem (solitary tract
nucleus of the medulla oblongata), which is part of the center that regulates heart rate and blood pressure (see also
Chapter 18). Signals are then relayed from the brainstem to the ADH-secreting cells of the supraoptic and
paraventricular hypothalamic nuclei. The sensitivity of the baroreceptor system is less than that of the osmoreceptors,
and a 5% to 10% decrease in blood volume or pressure is required before ADH secretion is stimulated. This is illustrated
in Figure 34-2, B. A number of substances have been shown to alter the secretion of ADH through their effects on
blood pressure, including bradykinin and histamine, which lower pressure and thus stimulate ADH secretion, and
norepinephrine, which increases blood pressure and inhibits ADH secretion. The sensitivity of the baroreceptor system
is less than that of the osmoreceptors, and a 5% to 10% decrease in blood volume or pressure is required before ADH
secretion is stimulated. This is illustrated in Figure 34-2, B. A number of substances have been shown to alter the
secretion of ADH through their effects on blood pressure, including bradykinin and histamine, which lower pressure and
thus stimulate ADH secretion, and norepinephrine, which increases blood pressure and inhibits ADH secretion.

5-10% Decrease in blood volume/pressure -> baroreceptors are stimulated -> signals sent by afferent fibers of vagus
and glossopharyngeal nerves to the brainstem -> activation of ADH-secreting cells to synthesize and release ADH ->
nerve impulses liberate ADH from axon terminals to posterior pituitary -> enter bloodstream -> retention of water ->
decrease urine output -> decrease water loss
2. Frank has chronic kidney disease stage 4. His creatinine is 3.8mg/dL, Na+ is 132 mmol/L and K+ is 6.5 mmol/L. He is
given salbutamol nebulizations.

a.) What are the factors that influence the distribution of K+ between the intracellular and extracellular compartment?

Potassium, being the major intracellular cation, is essential for cell growth, division, volume regulation, excitability of
nerve muscle cells, and contractility of cardiac, skeletal, and smooth muscle.

Physiologic Factors
-Epinephrine
Alpha-Receptors - stimulate K+ release (secretion) especially in the liver
Beta-Receptors - stimulate K+ uptake (reabsorption)
-Insulin
-stimulates uptake of K+ into cells
-stimulates NaKATPase pump -> move K+ into the cell
-most important hormone that shifts K+ into cells after ingestion of K+ in a meal
-Aldosterone
-stimulates uptake of K+ into cells
-also stimulates urinary K+ excretion

Pathophysiological Factors
-Acid-Base balance
-dec intracellular pH inhibits K+ uptake, lowering intracellular K+ and displaces K+ -> K+
exits cell (since when pH is lowered, H+ moves into the cell, K+ goes out to maintain electroneutrality
-Plasma osmolality
-inc osmolality enhances the release of K+ by cells (water leaves the cell due to inc
osmolality, causing the cell to shrink and increasing the K+ concentration inside the cell.
This provides a driving force for the exit of K+ from cells)
-Cell Lysis
-increase concentration of intracellular K+ -> driving force for the exit of K+ from cells
-Exercise
-More K+ is released from skeletal muscles during exercise

Drugs that induce Hyperkalemia


-Dietary K+ supplement
-ACE inhibitor
-K+ sparing diuretic
-Heparin

I feel like di na ito dapat kasama kasi balance between ICF and ECF lang eh, factors na ito for secretion sa kidneys, pero
sama na natin haha (better safe than sorry)

Physiologic factors increasing K+ secretion


- Plasma K+ concentration - stimulates NaKATPase -> inc K+ uptake across basolateral membrane which increases the
driving force for the of K+ across the apical membrane
-Aldosterone - increases amount of NaKATPase in the basolateral membrane and epithelial Na+ channels (ENaC) in the
apical membrane
-ADH - stimulates K+ secretion

Pathophysiologic factors increasing K+ secretion


-Tubular flow rate - increase Ca activates MAXI-K -> K+ secretion
-Acid-base balance
-Glucocorticoids
b.) Why was he given salbutamol nebulization?

Salbutamol also known as albuterol is a beta adrenergic agonist, specifically a β2 agonist. It is used commonly to treat
asthma attacks or COPD patients. However, this drug can also help lower the serum level of potassium of an individual.
As with the case of Frank who has chronic kidney disease stage 4, it is expected from him that his secretion of excess
potassium in the body is greatly impaired, thus causing hyperkalemia. Salbutamol was given because this agonist
stimulate the Na+ -K+ -ATPase pump of the cell through the activation of cAMP cascade, thereby allowing the potassium
to go inside the cell despite the fact that it is against its concentration gradient. With the influx of potassium inside
the cells, the level of potassium in the blood will in turn go down.

SGD 24: ACID-BASE

1. Using Figure 36-2 of Berne and Levy 6th edition, discuss bicarbonate reabsorption. What will happen to the
urine of a patient with congenital absence of brush border in the renal tubule?

Net acid excretion is maximized when little or no HCO3−is excreted in urine. Because HCO3−is freely filtered at the
glomerulus, approximately 4320 mEq/day is delivered to the nephrons and then reabsorbed. The proximal tubule
reabsorbs the largest portion of
the filtered load of HCO3−.
1. H+ secretion across the apical membrane of the cell occurs by both an Na-H+ antiporter and H-ATPase. The
Na-Hanti-porter (NHE3) is the predominant pathway for H+ secretion and uses the lumen-to-cell Na+ gradient to drive
this process
2. Within the cell, H and HCO3 are produced in a reaction catalyzed by carbonic anhydrase. His secreted into
tubular fluid, whereas HCO3−exits the cell across the basolateral membrane and returns to the peritubular blood.
3. Movement of HCO3 −out of the cell across the basolateral membrane is coupled to other ions. The majority of
HCO −exits via a symporter that couples the efflux of 1Na with 3HCO3 (sodium bicarbonate cotransporter: NBC1). In
addition, some of the HCO3−may exit in exchange for Cl−(via Na-independent and/ or Na-dependent Cl−-
HCO3−antiporters).
4. carbonic anhydrase is also present in the brush border of the proximal tubule cells. This enzyme catalyzes the
dehydration of H2CO3 in luminal fluid and thereby facilitates reabsorption of HCO3−.

The cellular mechanism for reabsorption of HCO3−by the thick ascending limb of the loop of Henle is very similar to
that in the proximal tubule. The distal tubule and collecting duct reabsorb the small amount of HCO3−that escapes
reabsorption by the proximal tubule and loop of Henle.

The the urine of a patient with congenital absence of brush border in the renal tubule...
2. Using Figure 36-5 of Berne and Levy 6th edition, discuss NH4+ production, transport and excretion. What will
happen if H+ secretion by the collecting duct is inhibited?
HCO3−reabsorption alone does not replenish the HCO3−lost during neutralization of the nonvolatile acids
produced during metabolism. To maintain acid-base balance, the kidneys must replace this lost HCO3−with new HCO3−.
Generation of new HCO3−is achieved by the excretion of titratable acid and by the synthesis and excretion of NH4. A
portion of new HCO3−generation occurs as a result of NH4 production and excretion.

NH4 is produced by the kidneys, and its synthesis and subsequent excretion add HCO3−to the ECF. Importantly, this
process is regulated in response to the acid-base requirements of the body. NH4 is produced in the kidneys via the
metabolism of glutamine. Essentially, the kidneys metabolize glutamine, excrete NH4, and add HCO3−to the body.
However, the formation of new HCO3−via this process depends on the kidneys’ ability to excrete NH4in urine. If NH4is
not excreted in urine but enters the systemic circulation instead, it is converted to urea by the liver. This conversion
process generates H, which is then buffered by HCO3−. Thus, production of urea from renally generated NH4 consumes
HCO3−and negates the formation of HCO3−through the synthesis and excretion of NH4 by the kidneys.

NH4is produced from glutamine in the cells of the proximal tubule, a process termed ammoniagenesis. Each glutamine
molecule produces two molecules of NH4and the divalent anion 2-oxoglutarate−2. Metabolism of this anion ultimately
provides two molecules of HCO3−. The HCO3−exits the cell across the basolateral membrane and enters the peritubular
blood as new HCO3−. NH4 exits the cell across the apical membrane and enters the tubular fluid. The primary
mechanism for secretion of NH4 into tubular fluid involves the Na-H antiporter, with NH4 substituting for H. In
addition, NH3 can diffuse out of the cell across the plasma membrane into tubular fluid, where it is protonated to NH4.

A significant proportion of the NH4 secreted by the proximal tubule is reabsorbed by the loop of Henle. The thick
ascending limb is the primary site of this NH4 reabsorption, with NH4 substituting for Kon the 1Na-1K-2Cl−symporter.
In addition, the positive transepithelial luminal voltage in this segment drives the paracellular reabsorption of NH4. The
NH4 reabsorbed by the thick ascending limb of the loop of Henle accumulates in the medullary interstitium. From there
it is then secreted into tubular fluid by the collecting duct. Two mechanisms for secretion of NH4by the collecting duct
have been identified. The first is nonionic diffusion and diffusion trapping. By this mechanism, NH3 diffuses from the
medullary interstitium into the lumen of the collecting duct. H secretion by the intercalated cells of the collecting duct
acidifies the luminal fluid (a luminal fluid pH as low as 4.0 to 4.5 can be achieved). Consequently, NH3 diffusing from the
medullary interstitium into the collecting duct lumen (nonionic diffusion) is protonated to NH4by the acidic tubular fluid.
Because the collecting duct is less permeable to NH4 than to NH3, NH4 is trapped in the tubule lumen (diffusion
trapping) and eliminated from the body in urine. The second mechanism involves NH4-H antiporters located in the
basolateral and apical membranes of the collecting duct cells). Because acidification of the tubular fluid drives both
nonionic diffusion and diffusion trapping, as well as secretion of NH4 across the apical membrane by the NH4-H
antiporter, the relative role of each mechanism to overall NH4 secretion is not known.
H+ secretion by the collecting duct is critical for the excretion of NH4+. If collecting duct H+ secretion is inhibited,
the NH4+ reabsorbed by the thick ascending limb of Henle’s loop will not be excreted in urine. Instead, it will be
returned to the systemic circulation, where as described previously, it will be converted to urea by the liver and
consume HCO3− in the process.
3. How do you compute for Anion Gap?
Anion gap (AG) represents the concentration of all the unmeasured anions in the plasma. The negatively charged proteins
account for about 10% of plasma anions and make up the majority of the unmeasured anion represented by the anion gap
under normal circumstances. The acid anions (eg lactate, acetoacetate, sulphate) produced during a metabolic acidosis
are not measured as part of the usual laboratory biochemical profile. The H+ produced reacts with bicarbonate anions
(buffering) and the CO2 produced is excreted via the lungs (respiratory compensation). The net effect is a decrease in
the concentration of measured anions (ie HCO3) and an increase in the concentration of unmeasured anions (the acid
anions) so the anion gap increases.

AG is calculated from the following formula:

Anion gap = [Na+] - [Cl-] - [HCO3-]

Reference range is 8 to 16 mmol/l. An alternative formula which includes K + is sometimes used particularly by
Nephrologists. In Renal Units, K+ can vary over a wider range and have more effect on the measured Anion Gap. This
alternative formula is:

AG = [Na+] + [K+] - [Cl-] - [HCO3-]

The reference range is slightly higher with this alternative formula. The [K +] is low relative to the other three ions
and it typically does not change much so omitting it from the equation doesn’t have much clinical significance.

A.

● Metabolic acidosis is generally defined by the presence of a low serum bicarbonate concentration (normal
range 22-28 mEq/L), although occasionally states can exist where the serum bicarbonate is normal with an
elevated anion gap (e.g., patients with a lactic acidosis who have received a bicarbonate infusion or patients on
hemodialysis). In general, a metabolic acidosis is associated with a low urine pH but depending on the presence
or absence of a respiratory alkalosis, this may also be normal or elevated. Thus, a patient can have an acidosis
but not be acidemic.
● Metabolic acidoses occur when there is excess acid in the plasma. In the basal state, the body generates about
12,000 to 13,000 mmol of carbon dioxide (CO2), and 1-1.5 mmol per kilogram body weight of nonvolatile acid.
The body has a large buffering capacity, with CO2-HCO3 as the major buffer system. The two major routes
of acid excretion are the lungs (for CO2) and the kidneys (for nonvolatile acids)
● A metabolic acidosis can be caused by three major mechanisms: 1) increased acid production; 2) bicarbonate
loss; and 3) decreased renal acid excretion
● Increased acid production leads to anion-gap (AG) metabolic acidosis, and involves a variety of different
clinical processes, see Table 1. An anion gap acidosis may also result for ingestion of an acid load.
● Both bicarbonate loss and decreased renal acid excretion lead to normal-anion gap (NG) metabolic acidosis.
When there is HCO3 loss, chloride is retained to maintain electrical neutrality. The different clinical
processes are summarized in Table 2.
● Toxic ingestions are common causes of AG metabolic acidosis. The commonest causes are methanol and
ethylene glycol intoxication. These alcohols are quickly absorbed from the GI tract. Peak serum levels are
usually reached within 1-2 hours. Immediately following ingestion, there is a large serum osmolar gap due to
the presence of unmeasured, small, non-charge molecules. However, as these parent alcohols go through a two-
step metabolism (via alcohol dehydrogenase and aldehyde dehydrogenase), the osmolar gap resolves while an
anion gap acidosis develops. The toxicities mainly come from their metabolites.
B.
● In hyperchloraemic acidosis, the anion-gap is normal (in most cases). The anion that replaces the titrated
bicarbonate is chloride and because this is accounted for in the anion gap formula, the anion gap is normal.
● If hyponatraemia is present the plasma [Cl-] may be normal despite the presence of a normal anion gap
acidosis. This could be considered a 'relative hyperchloraemia'. However, you should be aware that in some
cases of normal anion-gap acidosis, there will not be a hyperchloraemia if there is a significant hyponatraemia.

● The anion gap may still be within the reference range in lactic acidosis. Now this can be misleading to you when
you are trying to diagnose the disorder. Once you note the presence of an anion gap within the reference range
in a patient with a metabolic acidosis you naturally tend to concentrate on looking for a renal or GIT cause.

1. One possibility is the increase in anions may be too low to push the anion gap out of the reference range. In
lactic acidosis, the clinical disorder can be severe but the lactate may not be grossly high (eg lactate of 6mmol/l) and
the change in the anion gap may still leave it in the reference range. So the causes of high anion gap acidosis should be
considered in patients with hyperchloraemic acidosis if the cause of the acidosis is otherwise not apparent.
Administration of IV saline solution may replace lost acid anion with chloride so that treatment may result in the
acidosis converting to a hyperchloraemic type.

2. Another possibility is intracellular movement of acid anions in exchange for chlorid. In lactic acidosis, the
movement of lactate intracellularly in exchange for chloride occurs via an antiport. It has been found that when lactic
acidosis occurs in association with grand mal seizures then as many as 30% of this group of patients may present with a
hyperchloraemic component to their acidosis. This is an interesting situation because the lactic acidosis is due solely to
muscular over-production, occurs rapidly & can be severe BUT it also resolves rapidly. This should therefore be a pure
lactic acidosis initially without any respiratory compensation or evidence of other acid-base problem. So if we find a
hyperchloraemic component this clearly suggests that the lactate is being taken up by some cells in exchange for
chloride. This movement of the acid anion intracellularly is one mechanism responsible for a hyperchloraemic
component in some types of high anion gap acidosis.

3. The situation may also be due to the wide normal range of the anion gap. This could result in a situation where
the anion gap is only elevated slightly or still within the normal range due to the combination of small errors in the
measurement of the component electrolytes.