REGULATION OF RENAL BLOOD FLOW
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KIDNEY
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Filters the blood to remove waste
Receives ¼ of the blood that the heart pumps (1.25 L/min)
Blood from the renal artery flows into a smaller artery and
reach the tiniest arterioles (afferent arteriole) then reach the
tiny capillary bed called glomerulus (part of the functional unit
of the kidney – nephron)
Each nephron consists of:
o
Renal Corpuscle
➢ Glomerulus
➢ Bowman’s capsule
➢ Renal tubule
Once the blood leaves the glomerulus, it doesn’t enter into
venules instead the glomerulus funnels blood into efferent
arterioles which divide into capillaries a second time called
peritubular capillaries which are arranged around the renal
tubule
HORMONES THAT ↑ ARTERIOLAR RESISTANCE AND ↓ RENAL
BLOOD FLOW
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There are two key hormones that act to increase arteriolar
resistance and in turn reduce renal blood flow
o
ADRENALINE – also known as epinephrine is a
hormone secreted by the adrenal gland right above
the kidneys in response to sympathetic stimulation
➢ produces a fight-or-flight response by
binding to adrenergic receptors on cells
all over the body
➢ binds to the alpha-1 adrenergic
receptors along the afferent and efferent
arterioles and causes the smooth muscle
cells that wrap around those arterioles to
contract making the afferent and efferent
arterioles quickly constrict
➢ Example:
the
increased
arterial
resistance leads to a low renal blood flow
so when you’re being chased by a
kangaroo and the fight-or-flight mode is
on blood flow is basically diverted away
from the kidneys and towards more
important tissues like your leg muscles
o
ANGIOTENSIN II – synthesized in response to low
blood pressure by endothelial cells that line the
blood vessels throughout the body
➢ final product in a cascade of reactions
that start with renin
▪
RENIN – an enzyme produced
in the kidneys by specialized
smooth muscle cells called
juxtaglomerular cells which
can be found in the walls of the
afferent arterioles
➢ When there’s low blood pressure renin is
released in the blood where it cleaves
angiotensin 1 from angiotensinogen
➢ Endothelial cells in general but mostly
those lining the vessels in the lungs
make an enzyme called angiotensin
converting enzyme or “ACE” which
converts angiotensin 1 to angiotensin
2.
➢ Angiotensin II then travels through the
blood and when it reaches the kidneys, it
binds to angiotensin receptors along the
afferent and efferent arterioles. Just like
adrenaline, it causes those arterioles to
constrict and as before, the increased
arterial resistance leads to a low renal
blood flow
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There’s a mechanism to ensure that even though less blood
gets to the kidneys, glomerular filtration rate REMAINS
CONSTANT
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efferent
arterioles
are
much
MORE
RESPONSIVE to angiotensin ii than the afferent
arterioles
➢ when there are low levels of angiotensin
ii, only the efferent arterioles constrict
and this makes less blood leave the
glomerulus
BLOOD FILTRATION
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Blood filtration starts in the glomerulus where a urine
precursor called filtrate is formed.
GLOMERULAR FILTRATION RATE – amount of blood
filtered into the nephrons by all of the glomeruli each minute
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Glomerulus doesn’t allow red blood cells and
proteins to pass through and be excreted into urine
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What passes through the glomerulus is mostly
plasma which normally makes up about 55% of
blood
o
Glomerulus only filters about 20% of that plasma
in one go
➢ normally approximately 125 milliliters
This filtrate then enters the renal tubule
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renal tubule – made up of:
➢ proximal convoluted tubule
➢ nephron loop also known as the “loop of
henle” – has an ascending and a
descending limb and
➢ distal convoluted tubule
As filtrate makes its way through the renal tubule, waste and
molecules such as ions and water are exchanged between
the tubule and the peritubular capillaries until blood is
filtered of any excess
Peritubular capillaries reunite to form larger and larger
venous vessels
The veins follow the path of the arteries but in reverse so they
keep uniting until they finally form the large renal vein which
exits the kidney and drains into the inferior vena cava
RENAL BLOOD FLOW
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Renal blood flow is PROPORTIONAL to the pressure
gradient
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PRESSURE GRADIENT – difference in pressure
between the renal artery and the renal vein divided
by the resistance in the renal arterioles
(𝑝𝑟𝑒𝑠𝑠𝑢𝑟𝑒 𝑖𝑛 𝑟𝑒𝑛𝑎𝑙 𝑎𝑟𝑡𝑒𝑟𝑦 − 𝑝𝑟𝑒𝑠𝑠𝑢𝑟𝑒 𝑖𝑛 𝑟𝑒𝑛𝑎𝑙 𝑣𝑒𝑖𝑛)
𝑟𝑒𝑠𝑖𝑠𝑡𝑎𝑛𝑐𝑒 𝑖𝑛 𝑟𝑒𝑛𝑎𝑙 𝑎𝑟𝑡𝑒𝑟𝑖𝑜𝑙𝑒𝑠
o
↑ systemic blood pressure + ↓ resistance in the
renal arterioles = ↑ renal blood flow = ↑ glomerular
filtration rate
↓ systemic blood pressure + ↑ resistance in the
renal arterioles = ↓ renal blood flow = ↓ glomerular
filtration rate
REGULATION OF RENAL BLOOD FLOW – mainly
accomplished by increasing or decreasing arteriolar
resistance.
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➢
➢
it makes more blood remain in the
glomerulus thereby, preserving the
glomerular filtration rate
However, when there are HIGH LEVELS
OF ANGIOTENSIN II, both the afferent
and efferent arterials constrict and this
decreases both renal blood flow and
glomerular filtration rate
HORMONES THAT ↓ ARTERIOLAR RESISTANCE AND ↑ RENAL
BLOOD FLOW
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ATRIAL NATRIURETIC PEPTIDE or ANP – secreted by the
atria of the heart
BRAIN NATRIURETIC PEPTIDE or BNP – secreted by the
ventricles of the heart
o
named after the brain because it was first
discovered in pig brain extracts
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both ANP and BNP get secreted when there’s an increased
cardiac workload and the walls of the atria or ventricles
get stretched
o
They bind to specific natriuretic peptide
receptors expressed by smooth muscle cells and
initiate a cascade of intracellular events that result
in the dilation of afferent arterioles and the
construction of efferent arterioles, increasing
renal blood flow
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PROSTAGLANDINS – kidneys produce prostaglandin e2
and prostaglandin i2 in response to sympathetic stimulation
and it makes both the afferent and efferent arterioles dilate a
bit to make sure renal blood flow doesn’t get too low even
during those fight or flight situations
DOPAMINE – synthesized by cells in the brain and the
kidneys in the brain
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functions as a neurotransmitter in addition to that
in the brain and the rest of the body
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binds to specific dopaminergic receptors on
smooth muscle cells constricting the capillaries in
our skin and muscles and dilating the small vessels
around vital organs such as the heart and the
kidneys with vasodilation of both the afferent and
efferent arterioles
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↓ concentrations of dopamine = ↑ renal blood flow
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KIDNEY AUTOREGULATION
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Local mechanisms within the kidney that keep renal blood
flow and glomerular filtration rate CONSTANT over a range
of systemic blood pressures
Mechanisms that allow the kidney to adjust their own arterial
resistance to keep renal blood flow constant even when
blood pressure might range between 80 mmHg and 200
mmHg
Can be seen graphically when systolic blood pressure falls
below 80 mmHg
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renal blood flow is also low at 80 mmHg
Renal blood flow reaches an optimal value and the smooth
muscle cells in the arterial wall are completely relaxed
between 80 and 200 mmHg
Smooth muscle cells gradually become more constricted as
blood pressure rises maintaining a constant renal blood flow
above 200 mmHg
renal blood flow increases parallel to renal blood
pressure
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TWO MECHANISMS OF KIDNEY AUTOREGULATION
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MYOGENIC MECHANISM – arterial smooth
muscle reaction, which is based on a reflex of
smooth muscle cells to contract when they are
stretched by blood coming in at high pressures
➢ the more they get stretched by the blood
which is what happens when pressures
are high, the more they want to contract
which causes vasoconstriction of the
afferent and efferent arterioles
o
TUBULAR GLOMERULAR MECHANISM –
involves the distal convoluted tubule and the
glomerulus
➢ Part of the distal convoluted tubule loops
around and gets quite close to the
afferent arterial. This region where they
are in close contact is called the
juxtaglomerular apparatus with juxta
meeting next to the glomerulus
➢ In this region of the distal convoluted
tubule, there’s a group of cells collectively
called the macula densa
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macula densa cells can sense
when glomerular filtration
rate increases based on the
quantity of sodium and
chloride ions flowing through
the tubule
▪
When blood pressure rises,
renal blood flow and as a
consequence
glomerular
filtration rate also increases.
This means that there’s more
fluid and more dissolved
sodium and chloride ions
that reach the macula densa.
In response to the increased
fluid and sodium and chloride
ions, macula densa cells
release adenosine which
diffuses over to the nearby
afferent arteriole acting as a
paracrine
signal.
This
increases arteriolar resistance
and reduces the glomerular
filtration
rate
in
an
autoregulatory fashion
SUMMARY:
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ADRENALINE and ANGIOTENSIN II – increase arteriolar
resistance and decrease renal blood flow
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ATRIAL and BRAIN NATRIURETIC PEPTIDES – decrease
arteriolar resistance and increase renal blood flow
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In autoregulation, the kidneys keep blood flow constant
over a wide range of systolic blood pressures
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MYOGENIC MECHANISM – when smooth muscle
cells contract when stretched
o
TUBULAR GLOMERULAR MECHANISM – when
macula densa cells secrete adenosine which has a
paracrine effect on the afferent arteriole making it
vasoconstrict
➢
HYPOXIA
OXYGEN
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Cells use the oxygen to produce energy in the form of ATP, or
adenosine triphosphate
ADENOSINE TRIPHOSPHATE – important molecule, sometimes even
called “the molecular unit of currency”.
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Cells use it to basically pay the molecules inside the cell to do
their specific jobs.
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It’s like one big factory with a bunch of workers that all have
specific jobs needed to run the factory, and they only take ATP
as payment.
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Mitochondrion of the cell takes in oxygen and makes ATP to
pay the workers, through a process called oxidative
phosphorylation
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When the cell doesn’t get enough oxygen, and so payroll can’t
produce the ATP that they need to pay the workers to do their
jobs, the whole cellular factory can be damaged or even die,
and we call that process hypoxia
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hypo means “less than normal” and oxia means
“oxygenation”
When the oxygen comes in, typically it goes straight to payroll,
specifically to the inner mitochondrial membrane where
oxidative phosphorylation takes place.
Oxygen’s used in one of the last steps, and serves as an
electron acceptor, and this allows the process to finish and
produce ATP.
Without oxygen, we can’t finish oxidative phosphorylation and
produce ATP.
SODIUM POTASSIUM PUMP
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ANAEROBIC GLYCOLYSIS
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HYPOXIA
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➢
Pretty much like the bouncer that makes sure there isn’t too
much sodium diffusing into the cell, basically by pumping
it back out every time it diffuses in and maintaining a
concentration gradient
This process also keeps too many water molecules from
passively diffusing into the cell
Water molecules want to go every which way and are
constantly moving back and forth, inside and outside the cell,
but then all these sodium ions on this side tend to physically
block more of them from leaving that side, so over time more
water molecules get retained, or almost trapped, on the side
with more sodium—in short, the more sodium molecules:
the more water molecules.
Sodium Potassium Pump doesn’t do all this for free, and it
needs ATP. So without ATP, it stops pumping sodium back out,
and sodium diffuses in and the concentration gradient goes
away
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With less sodium particles on the outside blocking
the water molecules from going into the cell, water
follows sodium in, which causes the cell to swell
up.
o
When the cell swells up, a couple things happen:
➢ First, usually you have these really tiny
microvilli on the cell’s membrane, which
look sort of like little fingers that help
increase the cell’s surface area and
therefore help the cell absorb more
things, when the cell swells up and gets
all bloated, the water fills these little
fingers and REDUCES THE SURFACE
AREA, which makes it harder to absorb
molecules
Along the same lines, the cell can bleb,
or bulge outward from all this water, this
is a sign that the cell’s cytoskeleton or
this structural framework is beginning to
fail, and is letting water slip through.
The rough endoplasmic reticulum, or the
rough ER, also swells when the cell
swells.
▪
rough ER has all these little
ribosomes on its outside, and
these are really important for
the cell in making proteins, but
when the rough ER swells,
they detach, and stop making
proteins, so protein synthesis
goes down.
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All the ATP isn’t immediately lost when you lose oxygen and
oxidative phosphorylation stops, luckily your cell can make
ATP another way, called anaerobic glycolysis
anaerobic meaning in the absence of oxygen
Like the backup ATP generator, which, isn’t nearly as efficient
and only produces a net of about 2 ATP molecules per
glucose, whereas oxidative phosphorylation makes about
30-36
Produces the byproduct lactic acid, which lowers the pH
inside the cell.
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This more acidic environment can denature or
essentially destroy proteins and enzymes.
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Potentially reversible, meaning that if we all the
sudden get oxygen again and start making ATP,
then these changes aren’t necessarily permanent.
After enough time, though, irreversible damage
can happen to the cell.
CALCIUM PUMP
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Helps keep too much calcium from getting in, and if that
stops working, then calcium starts to build up, which isn’t a
great thing.
Calcium can activate certain enzymes that you might not
necessarily want to activate, like PROTEASES that can slice
up proteins and damage the cell’s cytoskeleton, which is
the structural framework that keeps the cell together.
ENDONUCLEASES can be activated, which can cut up
DNA, the cell’s genetic material.
As MORE LACTIC ACID BUILDS UP and the environment
gets more ACIDIC, the lysosomal membrane can be
damaged as well, which usually houses these hydrolytic
enzymes whose job is basically to grind up large molecules,
and when they get out, well, they’re also activated by calcium
and then they just start cutting’ everything in sight, and
basically start digesting the cell from the inside.
PHOSPHOLIPASE ENZYME, which basically splits
phospholipids
o
Since
the
cell’s membrane’s made
of
phospholipids, these can destroy the cell
membrane, which is probably the most important
sign of irreversible damage.
o
When the membrane’s destroyed, those enzymes
we just listed, along with others, can leak out into
the blood and continue wreaking havoc.
Calcium can get into the mitochondria, causing a cascade
the leads the mitochondrial membrane to be more permeable
to small molecules and so it lets a molecule that usually
stays in the mitochondrial, cytochrome c, to leak out into the
cytosol.
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Activates a process called apoptosis, or
programmed cell death.
PULMONARY EDEMA
o
PULMONARY EDEMA
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Refers to the buildup of fluid in the lungs including the
airways like the alveoli (tiny air sacs) as well as in the
interstitium (lung tissue that’s sandwiched between the
alveoli and the capillaries).
This space is mostly full of proteins, and when it starts filling
up with fluid, it can make it hard for oxygen to cross over
from the alveoli into the capillary, leaving the body hypoxic
- or deprived of oxygen.
THREE MAIN FACTORS THAT DETERMINE HOW FLUID MOVES
BETWEEN THE CAPILLARIES AND INTERSTITIAL FLUID,
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hydrostatic pressure
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oncotic pressure
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capillary permeability
1.
HYDROSTATIC PRESSURE – refers to the pressure felt by
fluid in a confined space, pushing the fluid OUT of that
space.
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In the interstitial space, it’s the same thing as the
blood pressure in the pulmonary capillaries, and
because the pulmonary circulation is a low pressure
system, the hydrostatic pressure is pretty low.
o
It’s still higher than the hydrostatic pressure exerted
by the interstitial fluid of the lungs - which is almost
zero.
o
If hydrostatic pressure was the only factor involved,
a lot of fluid would be continuously leaking out of
the pulmonary capillaries into the lung’s
interstitial space.
2.
ONCOTIC PRESSURE – a type of osmotic pressure exerted
by cells and proteins that can’t cross the capillary membrane
and therefore tend to ATTRACT fluid.
o
oncotic pressure is HIGHER in the pulmonary
capillaries than in the interstitial fluid, so it
opposes the hydrostatic pressure.
3.
CAPILLARY PERMEABILITY – or leakiness which affects
HOW EASILY fluid is actually able to GET THROUGH.
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When taking these three factors together, the net result is that
a very small amount of fluid leaks into the interstitial
space, and that fluid is normally whisked away by the
lymphatic channels in the lungs, which keeps the lungs free
of excess fluid.
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space of the lungs which leads to
pulmonary edema.
SEVERE
SYSTEMIC
HYPERTENSION
–
specifically a blood pressure that is greater than
180 systolic or 110 diastolic
➢ In this situation, the left ventricle is
healthy but simply can’t effectively pump
blood in a system with such HIGH
AFTERLOAD - in other words, under
conditions with such high systemic
pressures.
➢ Blood starts to BACK UP in the left
atrium, pulmonary veins, and pulmonary
capillaries,
ultimately
leading
to
pulmonary hypertension and pulmonary
edema
NON-CARDIOGENIC – typically involves damage to the
pulmonary capillaries or alveoli.
o
Noncardiogenic causes of pulmonary edema
include things like:
➢ PULMONARY INFECTIONS
➢ INHALATION OF TOXIC SUBSTANCES
➢ TRAUMA TO THE CHEST
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All of these can cause direct injury to the alveoli,
and when this happens, there is usually an
inflammatory process that makes nearby capillaries
MORE PERMEABLE. As a result, proteins and
fluid enter the interstitial space.
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SEPSIS – the key difference is that in sepsis the
inflammatory process happens THROUGHOUT
THE BODY rather than just in the lungs
➢ can cause extra fluid in the interstitial
space of tissues throughout the body.
o
LOW ONCOTIC PRESSURE – result from not
making enough proteins like albumin due to
malnutrition or from liver failure.
➢ Alternatively, it could be due to losing
protein too quickly like in nephrotic
syndrome.
➢ Leads to fluid moving from the capillary
and into the interstitial space throughout
the body, and in the lungs that results in
pulmonary edema.
DEVELOPMENT OF PULMONARY EDEMA
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UNDERLYING CAUSE OF PULMONARY EDEMA
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CARDIOGENIC – develops as a result of a heart disease
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The most common cardiogenic cause is LEFTSIDED HEART-FAILURE
➢ In left-sided heart failure, the left ventricle
becomes unhealthy and can’t pump
effectively, which means that blood
starts to BACKUP in the left atrium, and
then the pulmonary veins and pulmonary
capillaries.
➢ The extra blood in the pulmonary
capillaries
causes
pulmonary
hypertension – which is an increase in
the hydrostatic pressure of the
pulmonary blood vessels, and this
pushes more fluid into the interstitial
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often develops through a combination of mechanisms.
Pulmonary edema makes gas exchange DIFFICULT
because oxygen and carbon dioxide have to diffuse
through a wide layer of interstitial fluid, to get from the
alveoli to the pulmonary capillary and vice versa. That journey
can take too long relative to how quickly blood moves through
the lungs, and that makes it hard to fully oxygenate the blood.
Pulmonary edema can lead to severe shortness of breath,
and in left-sided heart failure, it can lead to orthopnea which
is when there’s worse shortness of breath while lying flat.
o
This happens because there’s INCREASED
PULMONARY CONGESTION while lying down,
and in left-sided ventricular heart failure, the
PULMONARY CIRCULATION IS ALREADY
OVERLOADED. As a result, the extra blood can’t
be pumped out efficiently, and it causes shortness
of breath.
o
This pulmonary congestion and shortness of breath
DECREASES when a person sits up.
DIAGNOSIS OF PULMONARY EDEMA
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chest x-ray
chest CT scan – shows fluid in the interstitial space
TREATMENT OF PULMONARY EDEMA
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supplemental oxygen
dependent on the underlying cause
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If the cause is cardiogenic in nature, medications
aimed at boosting the heart’s performance or
lowering the blood pressure can be helpful.
o
If the cause is related to inflammation or low
oncotic pressure, then managing that illness will
help resolve the pulmonary edema.
SUMMARY:
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PULMONARY EDEMA – refers to fluid accumulation in the
interstitial space of the lungs which can be seen on a chest
Xray or chest CT scan.
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Common CARDIOGENIC causes include left sided heart
failure and hypertension, both of which lead to INCREASED
hydrostatic pressure in the pulmonary capillaries.
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Common NON-CARDIOGENIC causes include inflammation
in the lungs or system-wide inflammation which causes the
pulmonary capillaries to be MORE PERMEABLE.
o
Other causes include a low oncotic pressure
which can be from malnutrition, liver failure, and
nephrotic syndrome.
o
Regardless of the cause, pulmonary edema
interferes with gas exchange and results in
shortness of breath.
This taking up more space issue triggers another mechanism
in our body that causes the hormone aldosterone to stop
being released.
o
LESS ALDOSTERONE floating around in the blood
causes the body to start dumping sodium from
the blood into the urine.
o
Concentration gradients cause water to follow
sodium, so we end up with the excess water being
excreted in the urine with the sodium,
normalizing the fluid volume in the blood. So now,
our body is removing sodium from blood that
already has a lower concentration of sodium.
This means the plasma sodium osmolarity is
DROPPING significantly.
SYNDROME OF INAPPROPRIATE ANTIDIURETIC
HORMONE (SIADH)
ANTIDIURETIC HORMONE
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Abbreviated as ADH, is the hormone that controls water
retention in the body.
Constrict blood vessels, and incidentally the vasoconstrictor
drug called vasopressin is just ADH.
The more ADH floating around in your blood, the more fluid
you retain.
o
↑ ADH = ↑ FLUID RETENTION
The less ADH in your blood, the more fluid you excrete.
o
↓ ADH = ↑ FLUID EXCRETION
This whole fiasco we’ve just talked about is called syndrome
of inappropriate antidiuretic hormone, often abbreviated as
SIADH.
NEPHRONS
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Structures that physically control how much water is
EXCRETED from your body.
Mostly a series of tubes attached end-to-end that type fluids
and wastes towards the bladder.
These tubes though also allow fluids and electrolytes to move
through the tube walls and back into the blood if needed.
ADH affects the last two-thirds of these tubes, called the distal
convoluted tubule and the collecting ducts.
o
These tubes focus almost exclusively on
REABSORBING water back into the blood.
o
The wall of these tubes are unsurprisingly made up
of cells, a common trait of living things, but these
cells have proteins called aquaporins.
➢ Aquaporins – allow water to move
quickly in and out of the cells.
➢ The more ADH floating around in the
blood, the more aquaporins are available
to facilitate water movement through the
cell.
↑ ADH = ↑ AQUAPORINS
➢ When ADH is low, most of the water flows
through the distal convoluted tubule and
the collecting duct, giving us diluted
urine (more water excreted)
➢ When ADH is high, aquaporins grab
much of the water passing through the
these tubes and throws them back into
the blood – diluted blood (more water
retained)
SAMPLE SCENARIO: When I drink a glass of water and that
water is absorbed into my blood, my plasma osmolality
drops, which means I’m diluting my blood with the water. That
means there’s more fluid for all those blood cells to bounce
around in. The part of my brain called the hypothalamus sees
this drop in plasma osmolality and tells the pituitary gland
to slow down the release of ADH.
o
Low ADH leads to lots of diluted urine (urine with
low osmolality), which brings our plasma osmolality
back to normal.
Suppose ADH continues to be released even though my
plasma osmolality has dropped. We’re going to continue
retaining water, and as we drink more and more water, we
might expect our plasma osmolality to continue dropping.
However this isn’t exactly the case.
o
As more water is retained, it dilutes the other
solutes floating around in our blood, like sodium.
o
The extra fluid also takes up more space in our
blood vessels.
FOUR PATTERNS OF ADH RELEASE IN PEOPLE WITH SIADH
1.
2.
3.
4.
Type A – completely erratic and is INDEPENDENT of the
plasma osmolality.
o
ADH levels tend to be very high so the maximum
amount of fluid is retained, causing urine
osmolality to be very high.
Type B – constant release of a moderate amount of ADH.
Type C – “baseline” plasma sodium concentration level is set
lower than normal.
o
This type is particularly unique because the plasma
sodium concentration is stable, unlike other
SIADH’s where it would continue to fall.
Type D – the least common type of SIADH where ADH
secretion is completely normal, yet urine osmolality is
still high.
SYMPTOMS OF SIADH
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The symptoms a person with SIADH experiences is caused
by the dilution and loss of sodium in the blood.
When your body has a lower sodium concentration than
normal, you experience symptoms similar to dehydration or
any other condition where sodium is low.
Symptoms like headaches, nausea, and vomiting are
common initially, along with muscle cramps and tremors.
As the sodium concentration continues to get lower in your
blood, the neurons in your brain begin to swell leading to
cerebral edema.
o
This causes symptoms like confusion, mood
swings, and hallucinations.
o
If left untreated it will lead to the common
downwards trend in most illnesses of seizure,
coma, death.
Low blood sodium levels and low plasma osmolarity
combined with high urine osmolality and high urine
sodium is a giant red flag for SIADH.
CAUSES OF SIADH
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Conditions like strokes, hemorrhages, or trauma to the brain
can mess up the brain’s ability to release ADH.
Some drugs that act on the brain like mood stabilizers or
anti-epileptics can change the way ADH is released.
Surgery in general often causes an increase secretion of
ADH.
o
Brain surgery, specifically to the pituitary gland also
might cause extra ADH to be released.
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ADH can also be produced ectopically by tumors, which
means the tumors themselves produce ADH outside of the
pituitary gland and release ADH into the bloodstream.
o
Small cell carcinoma in the lungs is the type of
cancer most likely to release ADH this way.
Infections in the lungs and brain are also linked to increase
the risk of ADH secretion.
Genetics – If some of your family members have had SIADH
before, there’s also a possibility you may develop it.
TREATMENT OF SIADH
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The best treatment for SIADH is to figure out what the
underlying cause of the excessive ADH is, and treat that
problem.
Restricting your daily intake of fluid
Start a high-salt and high-protein diet to help replace the
excess loss of sodium.
Drugs that inhibit ADH secretion can also be used in chronic
SIADH situations.
For people who have really severe acute hyponatremia
symptoms, hypertonic IV fluids are usually administered.
PRIMARY ADRENAL INSUFFICIENCY (ADDISON’S
DISEASE)
PRIMARY ADRENAL INSUFFICIENCY – also known as Addison’s
disease
•
Rare endocrine disorder that happens when the adrenal gland
isn’t able to produce enough of the hormones that the body
needs, particularly aldosterone and cortisol.
•
The reason it’s called “primary” is that the underlying problem
is localized to the adrenal gland itself, rather than a problem
of a hormone that acts on the adrenal gland or elsewhere in
the body.
•
Can develop acutely or chronically
•
•
•
ADRENAL GLAND
There are two adrenal glands, one above each kidney, and
each one has an inner layer called the medulla and an outer layer
called the cortex which is subdivided into three more layers:
•
ZONA GLOMERULOSA – outermost layer, and it’s full of
cells that make the hormone aldosterone
•
ZONA FASCICULATA – make the hormone cortisol as well
as other glucocorticoids
•
ZONA RETICULARIS - make a group of sex hormones called
androgens, including one called dehydroepiandrosterone,
which is the precursor of testosterone
pituitary gland, the pea-sized structure sitting just
underneath the hypothalamus.
o
In response, the pituitary gland sends out
adrenocorticotropic hormone, or ACTH, which
travels through the blood to the zona fasciculata of
the adrenal glands and signals cells there to release
cortisol.
Cortisol is a lipid-soluble molecule, meaning it can mingle
with fats, which allows it to easily pass through the plasma
membrane of cells and bind to the receptors inside.
Almost every body cell has cortisol receptors, so it affects
an huge variety of functions in the body
FUNCTIONS OF CORTISOL
o
Increase blood glucose levels by promoting
gluconeogenesis in the liver
▪
gluconeogenesis – formation of glucose
from noncarbohydrate sources, like
amino acids or free fatty acids.
o
Gets the muscles to break down proteins into
amino acids and gets adipose tissues to break
down fats into free fatty acids, both of which
provide the liver with more raw materials to work
with.
o
Keeps blood glucose levels high, and this is in
contrast top the hormone insulin, which causes
glucose to be taken up by various body tissues, and
so essentially cortisol acts to counteract this effect
this in an effort to make sure that the body can
respond appropriately to those raccoons, or other
stressors.
ALDOSTERONE
•
•
•
•
ANDROGENS
Part of a hormone family or axis which work together and are
called the renin-angiotensin-aldosterone system
Together these hormones decrease potassium levels,
increase sodium levels, and increase blood volume and
blood pressure
Secreted in response to elevated levels of renin, and it’s role
is to bind to receptors on two types of cells along the distal
convoluted tubule of the nephron.
FUNCTIONS OF ALDOSTERONE
o
Stimulates the sodium/potassium ion pumps of
the principal cells to work even harder. These
pumps drive potassium from the blood into the
cells and from there it flows down its concentration
gradient into the tubule to be excreted as urine. At
the same time, the pumps drive sodium in the
OPPOSITE DIRECTION from the cell into the
blood, which allows more sodium to flow from the
tubule into the cell down its concentration gradient.
Since water often flows with sodium through a
process of osmosis, water also moves into the
blood, which increases blood volume and
therefore blood pressure.
o
Stimulate the proton ATPase pumps in alphaintercalated cells which causes more protons to
get excreted into the urine. Meanwhile, ion
exchangers on the basal surface of the cell move
the negatively charged bicarbonate into the
extracellular space, causing an increase in pH.
CORTISOL
•
Needed in times of emotional and physical stress like
arguing with a friend or fleeing from a pack of raccoons.
o
In those situations, the hypothalamus—which is
an almond-size structure which sits at the base of
the brain, releases corticotropin-releasing
hormone is released from, and received by the
•
•
•
•
Adrenal glands are involved in testosterone production in
both men and women, but the amount that the adrenals
contribute is pretty small, relative to the testes in men, which
accounts for the very different levels of androgens in men
versus women.
In men, high levels of androgens are responsible for the
development of male reproductive tissues and secondary sex
characteristics like facial hair and a large larynx or Adam’s
apple.
In women, low levels of testosterone are responsible for a
growth spurt in development, underarm and pubic hair during
puberty, and an increased sex drive in adulthood.
The exact mechanism for adrenal androgen production is not
well understood, but like cortisol, it seems to be stimulated
by adrenocorticotropic hormone released from the pituitary
gland.
CAUSES OF PRIMARY ADRENAL INSUFFICIENCY
•
•
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AUTOIMMUNE DESTRUCTION – most common cause,
happens when the body’s own immune cells mistakenly
attack the healthy adrenal cortical tissues, though the
precise reason why this happens isn’t clear.
TUBERCULOSIS - most common cause in developing
countries; in this case the infection spreads from the lungs
to the adrenal glands, causing inflammation and destruction
in the adrenal cortex.
METASTATIC CARCINOMA – cancer spreads to the adrenal
cortex from somewhere else in the body. Regardless of the
cause, it turns out that the adrenal cortex has a high
functional reserve, meaning that a small amount of
functional tissue can still do a pretty decent job of churning out
enough of the hormones to meet the body’s needs. As a result
of this though, once there are symptoms, it’s usually a sign
that a majority, sometimes up to 90%, of the adrenal cortex
has been destroyed.
SYMPTOMS OF PRIMARY ADRENAL INSUFFICIENCY
•
•
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The symptoms of primary adrenal insufficiency correspond to
which layers of the adrenal cortex have been destroyed.
When the zona glomerulosa is destroyed, aldosterone
levels fall and that leads to high potassium levels in the
blood, or hyperkalemia, and low sodium levels in the blood,
or hyponatremia.
o
With less sodium around in the blood, water
moves out of the blood vessels, which results in a
low blood volume, or hypovolemia.
o
Fewer protons are lost, meaning more build up
in the blood and that results in an acidosis, and
more specifically a metabolic acidosis, since it’s
caused by the kidneys.
o
These electrolyte changes and hypovolemia can
cause symptoms like:
➢ cravings
for
salty
foods
with
simultaneous nausea and vomiting
➢ fatigue
➢ dizziness that worsens with standing
When the zona fasciculata is destroyed, cortisol levels fall
and that leads to inadequate glucose levels during times of
stress.
o
This means that while being chased by a pack of
raccoons, instead of feeling ready to sprint a person
might feel weak, tired, and disoriented.
o
Decreased levels of cortisol causes the pituitary
gland to become OVERACTIVE, since usually
cortisol has a negative feedback effect the pituitary
gland. So, it ends up producing proopiomelanocortin, which is a precursor to
adrenocorticotropic hormone, but it also turns
out to be a precursor to melanocyte-stimulating
hormone, the hormone that leads to skin pigment
production.
o
When the pituitary gland is overactive, it ends up
making more melanocyte-stimulating hormone,
resulting in hyperpigmentation, or darkening of
the skin, especially in sun-exposed areas and
joints, like the elbows, knees, and knuckles.
•
In some extreme cases of primary adrenal insufficiency, the
zona reticularis can be affected as well, and androgens
levels can fall.
o
This decrease doesn’t affect men much because
remember the testes are the major source of male
androgens. However, women can experience a loss
of pubic and armpit hair, as well as a decreased sex
drive.
•
Oftentimes, the slowly progressive chronic symptoms of
primary adrenal insufficiency are missed or ignored until a
major stressor, like a serious injury, surgery, or infection,
suddenly causes the symptoms to become really severe. In
other words the body has a sudden increased need for
aldosterone and cortisol, and the failing adrenal cortex
simply can’t deliver. This is known as addisonian crisis, or
acute primary adrenal insufficiency, and it usually happens
when the majority of the zona glomerulosa and zona
fasciculata are destroyed.
o
It can cause a sudden pain the lower back,
abdomen, or legs, with severe vomiting and
diarrhea, followed by dehydration; low blood
pressure; and loss of consciousness.
o
Left untreated, an addisonian crisis can be fatal.
o
Addisonian crises can also arise from WaterhouseFriderichsen syndrome, which is when a sudden
increase in blood pressure causes blood vessels in
the adrenal cortex to rupture, filling up the adrenal
glands with blood and causing tissue ischemia and
adrenal gland failure.
DIAGNOSIS OF PRIMARY ADRENAL INSUFFICIENCY
•
Primary adrenal insufficiency can be diagnosed with an
adrenocorticotropic hormone stimulation test.
o
During the test, a small amount of synthetic
adrenocorticotropic hormone is given, and the
amount of cortisol and aldosterone produced in
response is measured, which helps you figure out
how well the adrenal glands are working.
TREATMENT FOR PRIMARY ADRENAL INSUFFICIENCY
•
•
Usually individuals with primary adrenal insufficiency are
treated with hormones to make up for the lack of cortisol,
aldosterone, and androgens. T
hey typically have to be taken for the rest of an individual’s life,
and stopping the hormone replacements can lead to
Addisonian crisis.
SUMMARY:
•
PRIMARY ADRENAL INSUFFICIENCY - failure of the
adrenal cortex - specifically, the zona glomerulosa which
causes low aldosterone, as well as the zona fasciculata
which causes low cortisol, and in severe cases, the zona
reticularis, which causes low androgens.
HYDRATION
•
One mechanism is osmosis, where water moves from the
more dilute compartment or one with low concentration, to
the more concentrated compartment.
o
low concentration → high concentration
•
BLOOD OSMOLARITY - the overall concentration of all
substances dissolved in the blood like electrolytes, glucose,
and urea
o
good measure of hydration status, and it’s
normally around 300 (milliosmoles) mOsm per
liter.
o
When blood osmolarity is high, a common reason
is that there’s not enough water in the body, like
in dehydration.
o
When blood osmolarity is low, a common reason
is that there’s too much water - like when it’s being
retained by the kidneys.
WATER
•
Main substance in our bodies, making up more than 50% of
a person’s body weight, and it’s directly involved in every
biochemical reaction in each cell in our body.
Maintaining the right balance of water is what keeps us alive.
Water is a V-shaped molecule made up of two hydrogen
atoms that bind to a single oxygen atom, and it’s commonly
referred to by its chemical composition of H2O.
The bond between hydrogen and oxygen is a way of
representing the fact that the two atoms share a single
electron that zips around in the space between them.
o
The space where it moves around is called an
electron cloud and it’s a bit lopsided, since the
sharing isn’t completely balanced.
Because the electron spends a bit more time on the side
nearest the oxygen, the oxygen has a PARTIAL NEGATIVE
CHARGE and the hydrogens have a PARTIAL POSITIVE
CHARGE. That’s called a dipole, with the hydrogen end of
the bond having a slight positive charge, and the oxygen end
having a slight negative charge.
o
Dipole allows the slightly positive hydrogens to
line up with slightly negative oxygen atoms from
other water molecules.
o
That attraction between water molecules is called a
hydrogen bond, and ultimately it’s the reason that
water molecules huddle up together.
o
Having lots of slightly positive hydrogens and
slightly negative oxygens is what allows water to be
a great solvent for other molecules like sugar and
salt which can easily dissolve right into it.
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WATER INTAKE
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TWO MAJOR COMPARTMENTS OF TOTAL BODY WATER
Total body water can be subdivided into two major
compartments:
1. INTRACELLULAR FLUID – fluid inside cells, and
2. EXTRACELLULAR FLUID – fluid outside of cell like in the
blood and in the interstitial tissue between cells.
•
•
•
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A person’s total water makes up 60% of their body weight.
o
Two-thirds of that 60%, or 40% of body weight, is
intracellular fluid
o
The other 1/3 or 20% of body weight is
extracellular fluid.
Both inside and outside the cells, water acts as a solvent for
electrically charged molecules called ions or electrolytes.
When water dissolves electrolytes, the slightly negatively
charged oxygen attracts positive ions like sodium and the
slightly positively charged hydrogen attracts negative
ions like chloride.
•
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OSMOSIS
•
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MAIN POSITIVE
ELECTROLYTES
Sodium
Potassium
Calcium
Magnesium
•
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Normally, the amount of total body water is balanced through
ingestion and elimination of water - ins and outs.
About 80% of our water intake comes from drinking fluids the other 20% comes from food we eat.
o
Water content in food varies - but some fruits and
vegetables, like watermelon or strawberries, are
90% water by weight.
As far as water output goes, we eliminate water through
breathing, as humidified air leaves the body, as well as
through sweating, urinating, and with bowel movements.
The recommended daily amount of fluid intake for women is
around 11 glasses of water, or 2.2 L, and for men it’s about
13 glasses, or 3L.
PLAIN WATER – ideal choice when it comes to hydration, but
all fluids, including caffeinated drinks like coffee and tea, or
flavored waters and juices, contribute to water intake.
After we drink water, it travels all the way through our digestive
tract until it reaches the small and large intestines, where
water is absorbed into the bloodstream.
When we’re at rest, each heartbeat propels about 25% of our
blood to the kidneys, where millions of nephrons filter it to
produce urine.
When we’re properly hydrated, the kidneys produce between
800 and 2000 milliliters of urine every day, and the urine
has a pale yellow shade – like lemonade.
Some water, around 200 milliliters per day, is also lost
during bowel movements.
Sweat glands in the skin produce small amounts of sweat, and
their production increases when we’re nervous, when it’s
really hot outside, or during exercise.
o
The amount of sweat we lose each day varies quite
a lot based on the level of activity and the person,
so let’s say that on average it’s 500-700 milliliters
per day, even though some athletes can sweat
more than a liter in an hour when it’s really hot
“INSENSIBLE” WATER LOSSES
•
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MAIN NEGATIVE
ELECTROLYTES
Chloride
Bicarbonate
Phosphate
Sulfate
These are kept at very specific concentrations both within
and outside of the cell, through a variety of processes.
•
•
•
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They’re called insensible because we’re not aware of them.
When we breathe in, water inside our body is used to humidify
the air, and that water vapor is then lost when we breathe out.
Water also constantly diffuses through the layers of our
skin, keeping them elastic and nourished, but also
evaporating at the skin surface. This is in addition to losing
water through our sweat glands.
All in all, insensible losses account for an incredible 600-900
milliliters per day - which is a lot of water to lose without even
really sensing it.
children have improved concentration
and ability to focus.
✓ drinking more water can boost
children’s school performance
IMPORTANCE OF WATER
•
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Water makes up tears, mucus, saliva, and other secretions
that protect or lubricate passageways in and out of the body
like the eyes, nose, mouth, and genitals.
Lubrication – important in the pleural and pericardial
cavities in the chest and the peritoneal cavity in the
abdomen, where internal organs touch and slide over one
another.
o
It’s also needed at joints, where it helps form
synovial fluid that keeps our bones from rubbing
against one another.
Water is critical for digestion: the water in saliva moistens
food when we chew, while gastric and intestinal juices are a
fluid environment in which digestive enzymes break down our
meals.
Water forms the bulk of blood which allows oxygen and
glucose to move around the body, and plays a role in
eliminating toxins from the body through urination.
Water also helps regulate body temperature: when we’re
hot, like during a vigorous workout, the capillaries in our skin
dilate and sweat glands produce more sweat to dissipate heat.
On the other hand, when we’re cold, our blood vessels
constrict, retaining heat.
Water can also help with weight loss and maintaining a
healthy body weight.
o
Replacing sweetened drinks with water reduces
calorie intake, and drinking water before and during
a meal can increase our sense of fullness and
prevent overeating.
DEHYDRATION
•
when water losses are greater than the intake
•
CAUSES OF DEHYDRATION – ranging from vigorous
exercise or simply not drinking enough fluids throughout the
day, to vomiting, diarrhea, excessive sweating, or an inability
to swallow.
o
Sometimes dehydration can result from using
diuretics, or substances like alcohol or certain
medications.
o
Dehydration typically causes thirst, dry mouth and
lips, nausea, fatigue, and lightheadedness, as well
as a darkening of the urine color or a decrease
in urination.
o
A loss of as little as 2% of our body weight due to
water losses can lead to irritability, difficulty
concentrating, and headaches.
•
Some groups like children and the elderly are at increased
risk of dehydration.
o
CHILDREN
➢ Compared to adults, children have
lower body stores of water to begin
with, and they also have a higher
surface area to body mass ratio, so
they end up losing more water through
their skin.
➢ Children’s thirst sensors are not fully
developed, so they are less inclined to
drink water.
➢ Kids often depend on caregivers to
provide fluids, which makes it
challenging for them to meet their
hydration needs.
➢ Children between the ages of 4 and 13
need about 1.7 liters of fluid daily, and
research shows that well hydrated
o
•
ELDERLY
➢ Like children, they also have a
decreased thirst sensation
➢ May be taking medications that alter
their hydration status
➢ Oftentimes, they have chronic diseases
that affect their kidneys’ ability to maintain
a healthy water balance.
There are some circumstances in which a person, regardless
of age, might become dehydrated - like travelling on an
airplane or during extended strenuous physical activity.
o
Air inside airplanes is drier than the air on the
ground, so a flight over 2 hours can lead to
dehydration. Drinking fluids before and during a
flight can help prevent that.
o
Playing sports or doing heavy physical labor both of which make us sweat more - can lead to a
loss of both water and electrolytes. In the majority
of situations, water and electrolyte-containing foods
can help replace the losses, but replenishing with
an electrolyte-containing drink may help avoid
dehydration in longer-duration activities like running
a marathon or working outside in hot weather.
SUMMARY:
•
Most of our water intake comes from fluids, but we can also
get some of it from food.
•
We lose water in a number of ways – such as sweating,
breathing, urinating or defecating – and when those losses
are greater than our intake, dehydration can settle in.
•
The first signs of dehydration are:
o
sensation of thirst
o
dry mouth and lips
o
dark urine
o
difficulty concentrating
o
irritability.
•
The best way to avoid becoming dehydrated is to monitor
your urine color and drink fluids before you get thirsty –
once the thirst sensation is present, dehydration is already
underway.
o
Generally, drinking around 2 liters of water per
day is recommended – with more likely needed
more for males, people in dry or hot environments,
people who exercise, or people who perform heavy
physical labor.