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8/11/2019 Sia Dh Final

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SIADH

Most frequent cause of hyponatremia

First described by Schwartz et al in 1957 in 2 pts withbronchogenic carcinoma

Arginine vasopressin was then identified


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ADH

Synthesized in hypothalamus

Transported down to posterior pituitary Released in response to hyperosmolality (major stimuli,

mediated through osmoreceptors in hypothalamus) or

hypovolemia (via baroreceptors in left atrium, aortic arch, etc)


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ADH

Binds to V2 receptors in collecting tubules

stimulates cyclic adenosine monophosphate leads to insertion of aquaporin-2 channels into apical

membranes

The goal is to facilitate the transport of solute-free water


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Figure Freeze-fracture appearance ofvasopressin-induced intramembrane particle(IMP) aggregates in toad urinary bladder (A),

toad epidermis (B), and rat kidney collectingduct (C). The morphology of the aggregates isdifferent in all three vasopressin target cells. Inthe bladder, the aggregates are tightly packedlinear arrays, in the skin they form orthogonally

packed square arrays, and in the collectingduct principal cell they form loose clusters thatare often located in shallow depressions on thecell surface. Bar = 0.25 m.


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Figure Aquaporin-2 (AQP2) is internalized by clathrin-coated pits. Aand B,Immunogoldlabeling of AQP2 in clathrin-coated pits (arrows)at the apical plasma membrane ofcollecting duct principal cells. An antibody against an external epitope of AQP2 wasused. Cand D,Label-fracture images of LLC-PK1 cells expressing AQP2. Immunogold

label for AQP2 is located in intramembrane particle (IMP) clusters on the membrane (C,arrows; and is associated with membrane invaginations that resemble clathrin-coatedpits (D,arrows). For more details, see Sun TX, et al. Bars = 0.25 m.


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SIADH => SIAD

A slight misnomer

The name implies inappropriate secretion

1/3rdof pts do secrete AVP independent of plasma osmolality

Others exhibit reset osmostatAVP is fully supressed, butserum Na level is lower than nl

AVP levels may be undetectable in some pts

Some aquaporin mutations lead to concentrated urine in the

absence of AVP Therefore, the new term, Syndrome of Inappropriate

Antidiuresis (SIAD) has been proposed


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Patterns of plasma levels of arginine vasopressin (AVP; also known as the antidiuretic hormone), ascompared with plasma sodium levels in patients with SIAD, are shown. Type A is characterized by

unregulated secretion of AVP, type B by elevated basal secretion of AVP despite normal regulation by

osmolality, type C by a "reset osmostat," and type D by undetectable AVP. The shaded area

represents normal values of plasma AVP. Adapted from Robertson


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Disorders associated with SIAD

Malignancies

Carcinomas, lymphomas, sarcoma

Pulmonary disorders

Infectious, asthma, CF

CNS disorders

Infectious, bleeding, masses, MS

Drugs

Chlorpropramide, SSRIs, cyclophosphomide, ecstasy


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Diagnosis of SIAD

Essential features

hyponatremia

plasma osm100

clinical euvolemia

urinary Na>40

nl thyroid/adrenal fxn, no recent diuretic use


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Dx of SIAD

Supplemental features

uric acid


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Volume status assesment

Sometimes, clinical assesment of volume status is

imprecise. Dr. Berl suggests the following:

Rule out volume contraction by infusing 2L of NS over 24-48

hours.

Urine osm has to be less than 500 (to avoid severe worsening of

hypoNa)

If hypoNa corrects, this suggests volume depletion

NEJM 356:2064-2072


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Why 500 osms?

Where did Berl come up with that magic number?

Goldfarb and Rose both tell me that osmolality of

administered IVF must exceed osmolality of urine Who is right?


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Goldfarb-Rose Hypothesis

Prior acceptance that isotonic saline (308 osms) infusion in

SIAD is useless Electrolytes are excreted in urine

Urine osmolality in SIAD is typically >300

water is retained => worsening hypoNa


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Berls Axiom

Previous study showed an increase in plasma Na of pts with

SIADH from 124 to 127 mEq/l after IV NS (Musch et al Am J

Med 1995;99: 348-55) Mean initial urinary osmolality was 429 mosm/kg

So why not give SIAD pts isotonic saline?


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Treating SIADH with isotonic saline

Musch et al conducted a prospective study of 17 pts with

SIADH (Q J Med 1998; 91:749-753)

Goal to predict the response to isotonic saline based on either

Uosm and UNa+K

2L infusion over 24 hours

Initial plasma Na 115-130

All pts met the criteria for SIADH

Water restriction (


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Results

11 men, 6 women

mean age 64+13

Underlying conditions of 17 pts

Lung cancer (6) Other pulm diseases (4)

Cerebral traumatism (2)

Ovarian CA/sarcoma/cortical atrophia (1 each)

Idiopathic SIADH (2)


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Results cont.

t0 t24

Sodium 126+5 127+6

Potassium4+0.4 3.9+0.5

UNa+K 128+61 163+41

Uosm 502+128 497+113


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Weak correlation


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Strong correlation


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Discussion

11 / 17 pts increased their plasma Na after 2L infusion

Uosms exceeded the osmolality of isotonic saline

6 / 17 pts aggravated their hypoNa

mean Uosm > 538 mosm/kg


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Prvs assumption that rise in plasma Na by 5 mEq/L after 2L

NS infusion/24h suggests hypovolemia may be incorrect

This response can be observed in SIAD pts as well

Differentiate by high urinary salt excretion

salt-depleted hypovolemic pts conserve salt


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