Download Hypo_Hyperosmolar_States

Objectives
 Renal physiology
 Plasma osmolality vs effective osmolality
 Hypoosmolar state
 Hyponatremia (in most instances represents a
hypoosmolar state BUT not always!)
 More renal physiology!
 Regulation of antidiuretic hormone (ADH)
 Hyperosmolar states
 Hypernatremia
 Ingestions
Total Body Water (TBW)
 ~60% of lean body weight in men and ~50% in women
 Distribution


intracellular compartment (60% of TBW)
extracellular compartment (40% of TBW)
 Osmotic forces are the primary determinants of the
distribution of water between compartments
 Water flows from the compartment of low osmolality to
that of high osmolality until the osmotic pressures are
equalized
Osmotic Forces
 Each compartment has one major solute that is
restricted within its compartment and thus acts to
hold water within that space
 Na+ salts are the main extracellular osmoles
 K+ salts are the main intracellular osmoles
 In contrast, urea rapidly crosses cell membranes and
equilibrates throughout the TBW and thus does not
affect the distribution of water between the
intracellular and extracellular spaces.
Osmolality vs Effective Osmolality
 Osmolality: total number of particles in an aqueous
solution (mosmol/kg H2O)
 Normal Posm = 275-290 mosmol/kg
 Effective osmolality (tonicity): those particles that
can exert osmotic force across membranes, via
movement of water into or out of cells
 Examples: Na+, glucose, mannitol
 Normal effective Posm = 270-285 mosmol/kg
Plasma Osmolality
 Na+, glucose and BUN are major determinants of
plasma osmolality
 Posm = 2 x plasma [Na+] + [Glucose]/18 + [BUN]/2.8
 More important clinically to consider effective
osmolality than “total’’ osmolality
 Effective osmoles (Na+ , glucose) exert water shifts
unlike urea (as well as ethanol)
Comprehensive Clinical Nephrology, 4th Edition
Take Home Messages
 Increase in effective ECF osmolality results in cellular
dehydration
 Decrease in effective ECF osmolality results in cellular
overhydration
 Flow of water in and out of brain cells is primarily
responsible for clinical CNS manifestations
 Water shifts do not occur and symptoms of
hyperosmolality are absent when the effective
osmolality is not increased (ie in patients with uremia)
Take Home Messages
 Plasma [Na+] is a function of the ratio of the amounts
of solute and water present and does not necessarily
correlate with volume, which is a function of the total
amount of Na+ and water present
Hypotonic Hyponatremia
 Hypovolemic
 ↓ [Na+] = ↓↓TBNa/↓TBW
 Euvolemic
 ↓ [Na+] = ↔ TBNa/↑TBW
 Hypervolemic
 ↓ [Na+] = ↑TBNa/↑↑TBW
Plasma Osmolality
Does hyponatremia represent low
plasma osmolality in all cases?
NO
Plasma Osmolality
 Example
 Serum Na+ = 125 mEq/L
 BUN = 140 mg/dL
 Blood glucose = 90 mg/dL
 Calculated and measured osmolality = 305 mOsm/kg

Posm = 2 x 125 + 90/18 + 140/2.8
 In this case, hyponatremia is associated with an
elevated plasma osmolality
 Effective osmolality = 255 mOsm/kg (calculation
excludes BUN) thus this patient may have symptoms
of hypotonicity despite an elevated plasma osmolality
Plasma Osmolality
 Example:
 Serum Na+ = 133 mEq/L
 BUN = 11 mg/dL
 Blood glucose = 500 mg/dL
 Effective osmolality = 294 mOsm/kg (2 x 133 + 500/18)
 Hyponatremia is not always associated with
hypoosmolality ; thus direct therapeutic intervention
for hyponatremia may not be required (in this
example, need to treat underlying hyperglycemia)
Plasma Osmolality
Does plasma hypoosmolality
always represent hyponatremia?
YES
•Most of the plasma osmoles are Na+ salts, with lesser
contributions from other ions, glucose and urea
•Osmotic effect of the plasma ions (Posm) can be
estimated from 2 x plasma [Na+]
Plasma Osmolality
Do ineffective osmoles (urea, ethanol, ethylene
glycol, methanol) cause hyponatremia?
NO
Remember these osmoles readily move
between fluid compartments without
causing water shifts
Plasma Osmolality
Do effective osmoles (glucose,
mannitol) cause hyponatremia?
Yes
These osmoles shift water out of the cells
Clinical Examples of Hyponatremia
 Plasma Na+ = 120 mEq/L
 Blood glucose = 90 mg/dL
 BUN = 14 mg/dL
 Meas Posm = 250 mosmol/kg
Hypotonic hyponatremia: identify
some clinical conditions…
 risk of cerebral edema
Clinical Examples of Hyponatremia
 Plasma Na+ = 120 mEq/L
 Blood glucose = 90 mg/dL
 BUN = 14 mg/dL
 Meas Posm = 290 mosmol/kg
Pseudohyponatremia ( lipids, protein)
No risk of cerebral edema
Clinical Examples of Hyponatremia
 Plasma Na+ = 120 mEq/L
 Blood glucose = 1350 mg/dL
 BUN = 14 mg/dL
 Meas Posm = 320 mosmol/kg
Hyponatremia caused by hyperglycemia
No risk of cerebral edema
Clinical Examples of Hyponatremia







Plasma Na+ = 120 mEq/L
Blood glucose = 90 mg/dL
BUN = 14 mg/dL
Calc Posm = 250 mosmol/kg
Meas Posm = 325 mosmol/kg
Osmolar gap = 75 mosmol/kg
Effective osmolality = 320mosmol/kg
Dilutional hyponatremia caused by mannitol,
which results in an elevated osmolar gap
No risk of cerebral edema
Clinical Examples of Hyponatremia
 Plasma Na+ = 120 mEq/L
 Blood glucose = 90 mg/dL
 BUN = 14 mg/dL
 Calc Posm = 250 mosmol/kg
Beer Potomania
[EtOH] = 50 mmol/L
 Meas Posm = 300 mosmol/kg
 Osmolar gap = 50 mosmol/kg
 Effective osmolality= 245
mosmol/kg
 risk of cerebral edema
Clinical Examples of Hyponatremia
 Plasma Na+ = 120 mEq/L
 Blood glucose = 90 mg/dL
 BUN = 126 mg/dL
 Meas Posm = 290 mosmol/kg
 Effective osmolality = 245
mosmol/kg
Hyponatremia caused
by renal failure
 risk of cerebral edema
Note: a normal measured
plasma osmolality does
not preclude an increased
risk of cerebral edema
Laboratory Approach to
Hyponatremia
 Start with plasma osmolality to exclude
pseudohyponatremia (normal Posm) and hypertonic
hyponatremia (elevated Posm)
 When hypotonicity is confirmed, then clinically
evaluate the patients’ volume status
Causes of Hyponatremia
Current Medical Diagnosis & Treatment, 2009
Urine Osmolality
 Determine whether H2O excretion is normal or impaired
 Uosm > 100 mosmol/kg occurs in majority of
hyponatremic patients and indicates impaired H2O
excretion
 Uosm < 100 mosmol/kg indicates that ADH is
appropriately suppressed
 Primary polydipsia
 Low solute intake
 Reset osmostat
Reset Osmostat
• Normal osmotic responses to Posm but ADH release is
not suppressed until Posm falls well below normal (≠
SIADH in which there is nonsuppressible ADH
release)
• Plasma [Na] is subnormal but remains stable (usually
125-130 mEq/L)
• Associated with hypovolemia, psychosis, malnutrition,
quadriplegia and pregnancy
• Therapy for hyponatremia is unnecessary
Urine Sodium Concentration
 Una < 20 mEq/L
 Hypovolemia due to extra-renal losses
 Edematous states in CHF, cirrhosis, nephrotic syndrome
 Dilutional effect in primary polydipsia due to very high
urine output
 Una > 20 mEq/L
 Hypovolemia due to renal losses
 Renal failure
 SIADH
 Reset osmostat
Other Labs
 Plasma uric acid concentration
 Hypouricemia (< 4mg/dL) in SIADH

Mild hypervolemia decreases proximal Na+ reabsorption,
leading to increased urinary uric acid excretion
 Blood urea nitrogen
 BUN may be < 5mg/dL in SIADH

Mild hypervolemia leads to urinary urea wasting
Hyponatremia: Case
 62 year old woman noted an unpleasant, sweet taste in
her mouth. She otherwise felt well and was taking no
medications. Because dysgeusia is a rare manifestation
of hyponatremia, her serum sodium level was tested
and was 122 mEq/L.
What labs would you order?
Hyponatremia: Case (Cont)
 Measured Posm 250 mOsm/kg
 Urine osmolality 635 mOsm/kg
 Urine sodium 85 mEq/L.
 Her thyroid function and adrenal function were
normal
 A chest CT showed a mass in the lower lobe of the left
lung, which proved to be a small-cell carcinoma
Causes of SIAD
N Engl J Med 2007;356:2064-2072
Diagnosis of SIAD
N Engl J Med 2007;356:2064-2072
Antidiuretic Hormone
 Primary determinant of
free water excretion
 Increases water
permeability of the
luminal membranes of
the cortical and
medullary collecting
tubules, thus promoting
water reabsorption
(primarily in principal
cells)
Mechanism of Action
Libby: Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 8th ed.
Aquaporins
Transmission electron micrograph
illustrating immunogold labeling of
aquaporin-1 in the descending thin
limb (DTL) of a long-looped nephron
from rat kidney. Labeling of aquaporin1 is seen in both the apical and
basolateral plasma membrane. BM,
basement membrane. (Magnification,
×120,000.)
(From Nielsen S, Kwon TH, Christensen
BM, et al: Physiology and
pathophysiology of renal aquaporins. J
Am Soc Nephrol 10:647, 1999.)
Brenner: Brenner and Rector's The Kidney, 8th ed.
Osmoreceptor Control
 Osmoreceptors are specialized neurons in the
anterolateral hypothalamus
 The plasma [Na+] is the primary osmotic determinant
of ADH release
 Osmoreceptors are extremely sensitive and respond to
changes in plasma osmolality of as low as 1%
 Stimulation of ADH occurs when osmoreceptor cells
shrink in response to increased plasma osmolality
from effective osmoles (Na+, hyperglycemia, mannitol)
Osmotic
threshold
(2-5 mOsmol/kg)
Baroreceptor Control
 Afferent stimuli from carotid sinus
baroreceptors affect the activity of the
vasomotor center in the medulla and
subsequently ADH secretion by the cells
in the paraventricular nuclei
 Small changes in pressure or volume have
little effect on ADH release
Reduction of > 10%
blood volume
leads to
exponential
increase in ADH
release
Make sense
teleologically!
Control of ADH Secretion
Major stimuli to ADH secretion
are hyperosmolality (via
osmoreceptors) and effective
circulating volume depletion
(via baroreceptors)
V1
V2
+ decreased Posm
Hypernatremia
 Defined as serum [Na+] > 145 mEq/L
 Represents hyperosmolality
 Results from water loss (skin, respiratory and GI tracts,
dilute urine) or Na+ retention
 Defense against hypernatremia:
 ADH release
 Thirst


Provides ultimate protection against hypernatremia
Should never see an alert adult patient with serum [Na+] > 150
mEq/L who has normal thirst and access to water
Comprehensive Clinical Nephrology, 4th Edition
Comprehensive Clinical Nephrology, 4th Edition
Comprehensive Clinical Nephrology, 4th Edition
Hypernatremia: Case
 83 y/o female s/p emergent cholecystectomy for
acute cholecystitis with sepsis, 5 days ago. You are
called to see her for hypernatremia. She is very
weak and ill, and complains of thirst. Her water
pitcher is on the bedside table, which is pushed
against the wall in her room.
 PMH: HTN, HLD, OA
 PE: Ill appearing elderly female. T 101.2, BP 110/68,
P 95, Wt 54 kg. Mucous membranes dry. + drainage
bag in upper abdomen draining bile. + NG tube.
Dressed surgical wound. No edema.
Hypernatremia: Case
 Meds:
 D5 1/2 NS at 100 ml/hour
 TPN
 Aztreonam, Flagyl, Vancomycin (all in 0.9% NS)
 Labs: Na 155; K 4.6; HCO3 32; Cl 110; glucose 95;
BUN 45; creatinine 0.8
 Drainage bag output 100 ml/day; Urine output is
2.5 liters/day; Urine osmolality 516 mOsm/kg
Etiologies of this patient’s hypernatremia?
 Unable to access water
 Hypotonic fluid losses:
 NG and biliary drainage
 Increased insensible losses due to fever
 Averages 800-1000 ml/day in adults
 Estimation: 15 ml/kg/day; 15% increase for each 1 ̊C
 Fever, respiratory infections, burns increase insensible losses
 ? Mild renal insufficiency results in suboptimal urinary
concentration (Uosm 516 mOsm/kg)
 Hypertonic gains: total parenteral nutrition
(hyperosmotic), 0.9% NS used for antibiotics
What’s her free water deficit?
 [Na+] [TBW] desired = [Na+] [TBW] actual
 [140 mEq/L] [TBW] = [155 mEq/L] [0.5 (54kg)]
 [TBW] desired = 29.9kg
 Free water deficit= 29.95kg – 27kg= 2.9kg
 Replace ½ of deficit with free water over 24 hours
 Lower serum [Na+] no more than 10 mEq/L over 24
hours
 Also need to take into account daily insensible losses
and free water loss via urinary and GI tracts.
Does she have an osmotic diuresis?
 Osmotic diuresis: increased urinary water loss induced
by the presence of large amounts of nonreabsorbed
solute in the tubular lumen (resulting in hypotonic
urine)
 How many osmoles a day is she excreting in her urine?
 516 mOsm/Kg x 2.5 liter/day = 1290 mOsm/day
 An average person excretes about 600-900 mOsm/day
 The high urinary osmolar excretion likely accounts for
the elevated urine osmolality, due to a high urea
concentration from the high protein TPN
 The high urine [urea] results in an osmotic diuresis
Comprehensive Clinical Nephrology, 4th Edition
Toxic Alcohol Ingestions: Case
 A 38-year-old man presented to the emergency
department after reportedly ingesting antifreeze.
 He appeared to be intoxicated and was agitated and
combative; chemical sedation was induced.
 Initial laboratory studies revealed a pH of 7.0, an anion
gap of 22 mmol per liter, and an osmolar gap of 79
mOsm.
N Engl J Med 2007;356:6
Urine Fluorescence on Wood’s Lamp
N Engl J Med 2007;356:6
Calcium oxalate dihydrate
Comprehensive Clinical Nephrology, 4th Edition
Calcium oxalate monohydrate
Comprehensive Clinical Nephrology, 4th Edition
Needle-shaped monohydrate crystals
(a) The urine sediment
with multiple refractile,
needle-shaped crystals,
which in (b), using a
polarizer, shows
birefringence (original
magnification 40).
Kidney International 2008; 73: 1201–1202
Osmolar Gap
 Osmolar gap = measured Posm – calculated Posm
 Posm (mOsm/L) = 2 x plasma [Na+] + Glucose
(mg/dL)/18 + BUN (mg/dL)/2.8
 Measured Posm is usually within 10 mOsm/L of the
calculated Posm
 Elevated osmolar gap:
 Alcohol ingestions: methanol, ethanol, isopropanol,
ethylene glycol, propylene glycol, diethylene glycol (OG
> 20 mOsm/L)
 Diabetic or alcoholic ketoacidosis, lactic acidosis, renal
failure (OG < 15-20 mOsm/L)
Osmolar Gap: Pitfalls
 The plasma osmolal gap cannot distinguish among
various alcohol ingestions
 Absence of an osmolar gap does NOT exclude an
alcohol-related intoxication
 The plasma osmolal gap increases only in the presence
of the parent alcohols. The toxic acid metabolites of
methanol and ethylene glycol do not contribute to the
calculated osmolal gap. As a result, the plasma osmolar
gap is insensitive in late presentations, since most of the
parent alcohol has already been metabolized.
Evolution of changes in the serum osmolal and anion
gaps during the course of methanol intoxication.
CJASN 2008;3:208-225
Metabolic pathways for ethanol, methanol, and
ethylene glycol
CJASN 2008;3:208-225
Metabolic pathways for isopropanol, diethylene glycol,
and propylene glycol
CJASN 2008;3:208-225
©
Clinical and Laboratory
Disorder
Substance(s) Causing Toxicity
Abnormalities
Alcoholic (ethanol) ketoacidosis β-hydroxybutyric acid,
Metabolic acidosis
Acetoacetic acid
Methanol intoxication
(windshield wiper fluid, model
airplane fuel, antifreeze)
Formic acid, Lactic acid,
Ketones
Ethylene glycol intoxication
(antifreeze, runway deicers)
Glycolic acid, Calcium oxalate
Diethylene glycol intoxication
(brake fluid)
2-Hydroxyethoxyacetic acid
Propylene glycol intoxication
(solvent for hydralazine,
nitroglycerin, lorazepam,
diazepam, phenytoin,
phenobarbital, digoxin)
Isopropanol intoxication
(rubbing alcohol)
Lactic acid
Isopropanol
Comments
May be most frequent alcoholrelated disorder; mortality low
relative to other alcohols;
rapidly reversible with fluid
administration; increase in
SOsm inconsistent
Metabolic acidosis,
Less frequent than ethylene
hyperosmolality, retinal damage glycol; hyperosmolality and high
with blindness, putaminal
anion gap acidosis can be
damage with neurologic
present alone or together;
dysfunction
mortality can be high if not
treated quickly
Myocardial and cerebral damage More frequent than methanol
and renal failure; metabolic
intoxication; important cause of
acidosis, hyperosmolality,
intoxications in children;
hypocalcemia
hyperosmolality and high anion
gap acidosis can be present
alone or together
Neurological damage, renal
Very high mortality possibly
failure, metabolic acidosis,
related to late recognition and
hyperosmolality
treatment; most commonly
results from ingestion in
contaminated medications or
commercial products;
hyperosmolality may be less
frequent than with other
alcohols
Metabolic acidosis,
May be most frequent alcohol
hyperosmolality
intoxication in ICU; minimal
clinical abnormalities; stopping
its administration is sufficient
treatment in many cases
Coma, hypotension,
Hyperosmolality without
hyperosmolality
acidosis; positive nitroprusside
reaction
CJASN 2008;3:208-225
Disorder
Methanol intoxication
Epidemiology
Diagnostic Cluesb
Accidental or intentional
Osmolal gap with HAGAc
ingestion of adulterated alcohol Visual difficulties with optic
or products with methanol; rare papillitis
cases of inhalation of methanol
Ethylene glycol intoxication
Accidental or intentional
ingestion of antifreeze, alcohol
adulterated with ethylene
glycol, or products with
ethylene glycol
Osmolal gap with HAGAc
ARF with osmolal gap
Calcium oxalate crystals in
urine, monohydrate or
dihydrate
Blood pH <7.1; glycolate level >8
to 10 mmol/L; ARF requiring
HD; diagnosis >10 h after
ingestion; serum ethylene glycol
>50 to 100 mg/dl
Diethylene glycol intoxication
Ingestion of contaminated
medication or products with
diethylene glycol
Osmolal gap with HAGAc
Osmolal gap with ARF
Osmolal gap with coma
Blood pH <7.1; ARF requiring
HD; severe coma; ingestion of
>1.34 mg/kg body wt
Propylene glycol intoxication
Intravenous administration of Osmolal gap with or without LA Severe LA; serum propylene
medication with propylene
glycol level >400 to 500 mg/dl
glycol; rare ingestion of
products with propylene glycol
Isopropanol intoxication
Accidental or intentional
ingestion of rubbing alcohol
Osmolal gap without HAGA
Alcoholic ketoacidosis
Binge drinking often in
alcoholic patients associated
with starvation and often
vomiting
HAGA, trace positive or
Blood pH <7.0; severe comorbid
negative nitroprusside reaction conditions
with increase with H2O2;
hypoglycemia; osmolal gap
Poor Prognostic Factors
Blood pH <7.1; LA; severe coma;
severe hypotension; serum
methanol >50 to 100 mg/dl
Severe LA; hypotension; serum
isopropanol level ≥200 to 400
mg/dl
CJASN 2008;3:208-225
Fomepizole has ~500-1000x greater affinity
for ADH than ethanol
N Engl J Med 2009;360:2216-23
General Principles in the Treatment
of Alcohol Intoxications
Gastric lavage, induced emesis, or use of activated charcoal
to remove alcohol from gastrointestinal tract needs to be
initiated within 30 to 60 min after ingestion of alcohol
Administration of ethanol or fomepizole to delay or prevent
generation of toxic metabolites needs to be initiated while
sufficient alcohol remains unmetabolized measurement of
blood alcohol concentrations and/or serum osmolality can
be helpful
Dialysisb (hemodialysis > continuous renal replacement
therapy > peritoneal dialysis) helpful in removing
unmetabolized alcohol and possibly toxic metabolites and
delivering base to patient to ameliorate metabolic acidosis
Disorder
Methanol intoxication
Ethylene glycol intoxication
Diethylene glycol intoxication
Propylene glycol intoxication
Isopropanol intoxication
Alcoholic ketoacidosis
Treatmentb
Initiate fomepizole (alcohol if fomepizole not available) and HD
with methanol >20 mg/dl, in presence of HAGA with osmolal
gap and high suspicion of ingestion. Initiate HD alone if HAGA
present and methanol levels <10 mg/dl or no osmolal gap but
strong suspicion of ingestion. Give folinic or folic acid. Give base
with severe acidosis if patient not undergoing HD. Discontinue
treatment when pH normalized and methanol levels <10 to 15
mg/dl or undetectable. If measurement of methanol not
available use return of blood pH and serum osmolality to
normal as goals of therapy.
Initiate fomepizole (alcohol if fomepizole not available) and HD
with ethylene glycol levels >20 mg/dl or in presence of HAGA
with osmolal gap and high suspicion of ingestion. Initiate HD
alone if HAGA present and ethylene glycol level <10 mg/dl or no
osmolal gap but strong suspicion of ingestion. Give base with
severe acidosis if patient not undergoing HD. Give thiamine and
pyridoxine. Discontinue treatment when pH normalized and
ethylene glycol levels <10 to 15 mg/dl or undetectable. If
measurement of ethylene glycol not available use return of
blood pH and serum osmolality to normal as goals of therapy.
Initiate HD with osmolal gap, HAGA, and ARF or with high
suspicion of ingestion because of cohort of cases ingesting
contaminated medication. Administration of fomepizole not
approved but recommended in addition to dialysis.
Discontinuation of treatment with recovery of renal function,
normalization of acid-base parameters and osmolal gap.
Discontinue medication containing propylene glycol which will
be effective alone in most cases. Initiate dialysis and/or
fomepizole with severe LA or very high serum concentrations
>400 mg/dl and evidence of severe clinical abnormalities.
Supportive therapy usually sufficient. Initiate HD with serum
level 200 to 400 mg/dl or in presence of marked hypotension or
coma.c
Administer intravenous fluids including dextrose and NaCl; base
rarely needed, might be considered with blood pH <6.9 to 7.0;
consider administering insulin with marked hyperglycemia
Pseudohyponatremia
Serum [Na+] = 140 mEq/L
Serum [Na+] = 130 mEq/L
Solids 7%
1 liter
plasma
1 liter
plasma
Solids 14%
HYPERLIPIDEMIA
Water
93%
HYPERPROTEINEMIA
Na+
140 mEq
in 930 ml
Water
86%
OSMOLALITY
Measures solute per unit plasma water
140 mEq/930 ml = 151 mEq/liter = 130 mEq/860 ml
Na+ 130 mEq
in 860 ml
Other factors affecting ADH secretion
 Nausea
 Extremely potent stimulus (as much as 500-fold rise in ADH
level)
 Hypoglycemia
 3-fold rise in ADH level when plasma glucose decreases by 50%
 Pregnancy (reset osmostat)
 Lowers the osmoregulatory threshold for ADH release and
thirst
 Fall in plasma [Na+] by about 5mEq/L
 May be mediated by ↑release of chorionic gonadotropin which
causes systemic vasodilation and fall in BP
 Multiple drugs (i.e. morphine, nicotine, cyclophosphamide)