Syndrome of inappropriate anti diuretic hormone secretion (siadh) Diagnosis SIgns and Symptoms Treatment

1. Syndrome of Inappropriate
Anti-diuretic Hormone
(SIADH)

2.  A disorder which causes hyponatremia and hypo-
osmolality resulting from inappropriate, continued
secretion or action of the ADH despite normal or
increased plasma volume, which results in impaired
water excretion.

3. •Arginine vasopressin (AVP) –Naturally occuring ADH in humans –
Synthesized in the anterior hypothalamus, and transported to the
posterior pituitary
•Stimuli for AVP secretion:
–Hyperosmolarity – sensed by osmoreceptors in the hypothalamus
–Circulating volume depletion – sensed by baroreceptors in carotid
sinus, aortic arch and left atrium

4. ADH receptors
•V1a –Stimulates vasoconstriction
•V1b –Stimulates ACTH secretion
•V2 – Insertion of the water channel aquaporin-2 in the luminal
membrane of the collecting duct, thus making it more permeable to
water

5. ADH
•Normally, when plasma osmolality falls <275 mOsm/kg, AVP
secretion stops. –increases water excretion, which leads to a dilute
urine with an osmolality of 40-100 mOsm/kg.
•When plasma osmolality rises (or 8-10% reduction in circulating
volume), AVP secretion increases. –increase in water reabsorption
and an increase in urine osmolality to as much as 1400 mOsm/kg.

6. Pathogenesis
 The release of ADH is not inhibited by a reduction in plasma
osmolality.
• The nonphysiological secretion of AVP results in enhanced water
reabsorption, leading to dilutional hyponatremia.
 Transient expansion of ECF volume.
• Volume receptors are activated and natriuretic peptides are
secreted, which causes natriuresis and some degree of
accompanying kaliuresis.

7. SIADH
•Hyponatremia
•Inappropriately elevated urine osmolality (>100 mOsm/kg)
•decreased serum osmolality in a euvolemic patient, in the setting
of: –normal cardiac, renal, adrenal, hepatic, and thyroid function; –in
the absence of diuretic therapy; –in absence of other factors known
to stimulate ADH secretion, such as hypotension, severe pain,
nausea, and stress.

8. Pathophysiology
 Hyponatremia and hypo-osmolality cause acute cerebral
edema.
 Brain ECF moves into CSF –Brain cells lose potassium,
amino acids like glutamate, glutamine, taurine,
myoinositol and creatinine
 Following correction of hyponatremia –Overshoot of
electrolytes in 24 hours –Return to normal slowly over 5-
7 days
 Rapid correction of hyponatremia (>0.5 mEq/L/h) –Lost
electrolytes cannot be restored as rapidly –Osmotic
demyelination

9. Patterns of ADH secretion
•Type A –Erratic, unregulated release of ADH –No relation to plasma
osmolality
•Type B –Modest and constant leak of ADH
•Type C –Downward resetting of the osmostat –Plasma Na
concentration is normally regulated and is stable at a lower level
(125-135 mEq/L)
•Type D –Normal ADH secretion –Urine is still concentrated –Germ
cell mutation in which V2 receptor is activated –Production of an
antidiuretic compound other than AVP

10. 12.
Etiology
•CNS disturbances –Stroke, hemorrhage, infection, trauma,
psychosis
•Malignancies –Small cell carcinoma of lung –Head and
neck malignancies –Olfactory neuroblastoma –
Extrapulmonary small cell carcinoma

11. •Drugs –Chlorpropamide –Carbamazepine –
Cyclophosphamide, vincristine, cisplatin, methotrexate
 SSRIs – fluoxetine, sertraline
 MAO inhibitors –NSAIDs, opiates
 Sodium valproate
 –INF alpha, INF gamma

12.  Surgery –Trans-sphenoidal pituitary surgery
•Inappropriate ADH release from the injured posterior pituitary
•Fall in plasma Na is most severe on 6th-7th post-op day
•Pulmonary disease –Pneumonia, asthma, pneumothorax
•Hormone deficiency –Hypopituitarism, hypothyroidism
•Iatrogenic –Desmopressin – for von Willebrand disease or
hemophilia –Oxytocin –Vasopressin – for control of GI bleeding

13. Presentation
 Depending on the magnitude and rate of development,
hyponatremia may or may not cause symptoms.
•Signs and symptoms of acute hyponatremia do not
precisely correlate with the severity or the acuity of the
hyponatremia.
Some patients may be relatively asymptomatic.

14. •When serum sodium <125 mEq/L –Anorexia, nausea,
malaise
•Further decrease –headache, muscle cramps, irritability,
drowsiness, confusion, weakness, seizures, and coma
•Symptoms from CNS or pulmonary tumors –hemoptysis,
chronic headaches

15. Physical examination
•Euvolemic and normotensive
•No edema or dry mucous membranes or reduced skin
turgor
•Severe or rapid-onset hyponatremia –delirium, muscle
weakness, myoclonus, hyporeflexia, dysarthria, Cheyne-
Stokes respiration, generalized seizures, and coma.

16. Laboratory tests
•Serum sodium: <135 mmol/L
•Serum potassium: unchanged
•Urinary Na excretion: >20 mmol/L
•Urinary osmolality: >100 mOsm/kg
•BUN: <10 mg/dL
•Serum uric acid: <4 mg/dL
•GFR: increased

17. Imaging
 Chest X-ray –To find out an underlying pulmonary cause
(CT and MRI)

18. Management
•Treatment of the underlying disease, if possible •Initial
therapy to raise the serum sodium •Prolonged therapy in
patients with persistent SIADH
•Hormone replacement in adrenal insufficiency or
hypothyroidism
•Treatment of infections such as pneumonia, meningitis or
tuberculosis
•Cessation of offending drugs

19. Emergent Care
•Correction of hyponatremia –Aggressive treatment vs risk
of inducing central pontine myelinolysis
•Aggressive management –In case of seizures, stupor,
coma, respiratory arrest regardless of the degree of
hyponatremia

20. •Correction of hyponatremia at a rate that does not cause neurologic
complications –Raise serum Na levels by 0.5-1 mEq/h, and not more
than 10-12 mEq in the first 24 hours –To bring Na value to a
maximum of 125-130 mEq/L
•3% hypertonic saline
•Furosemide –Increases free water excretion –Limits treatment-
induced volume expansion

21. •Combining –Furosemide –hypertonic saline –water
restriction may lead to a faster rate of correction of serum
Na
•Requires frequent checking of serum Na+ osmolality and
urine osmolality

22. Acute Setting
•< 48 hours since onset
-Moderate symptoms like confusion, disorientation, nausea,
vomiting
-Treatment options –3% hypertonic saline –Loop diuretics
with saline –Vasopressin-2 receptor antagonists –Water
restriction
•Acute onset and moderate neurological symptoms –3%
hypertonic saline
•Less severe symptoms (headache, irritability, altered
mood) or no symptoms –Vasopressin-2 receptor
antagonists –Water restriction

23. Water restriction
 Mainstay of therapy
• Water restriction depends on –prior water intake –
expected ongoing fluid losses –degree of hyponatremia
• 500 – 1500 mL/day
• In case of subarachnoid hemorrhage –Fluid restriction
reduces BP and promotes cerebral vasospasm and
infarction –Treated with hypertonic (3%) saline

24. Vasopressin receptor antagonists
•Inhibition of V2 receptor (Aquaretics) –Reduces the
number of aquaporin-2 water channels in the collecting
duct, reducing its water permeability
•Vaptans –Conivaptan –Tolvaptan

25. Vaptans
 Conivaptan –Parenteral dual V1a- and V2-receptor
antagonist –20mg loading dose, followed by continuous
infusion or as intermittent boluses
•Should not be used for more than 4 days –Conivaptan + 2
L fluid restriction over 4 days
•Increased serum Na by 6 mEq/L

26. •Tolvaptan –Oral V2 receptor antagonist –Started at 15mg daily and
titrated up to 60 mg daily as required –Tolvaptan + fluid restriction
•Increased serum Na by 8 mEq/L over 30 days –Patient can be
discharged in 24-48 hours if neurological symptoms have resolved –
Drug can be withdrawn after 2-4 weeks, while carefully monitoring
serum Na daily for the next 5 days

27. Vaptans: benefits & risks
•Benefits:
–prompt correction of serum Na+
–producing water excretion without electrolyte excretion
–eliminating the need for fluid restriction.
•Risk
–excessively rapid rate of correction of serum Na.

28. Chronic Hyponatremia
•Fluid restriction
•V2 receptor antagonists
•Loop diuretics
•Urea
•Mannitol
•Demeclocycline

29. Urea
•Increases urinary loss of water along with urea, and
decreases free water retention
•Can be administered on a long-term basis (0.5 g/kg body
weight) as a powder dissolved in water along with meals
•Can also be given via G tube or IV in patients with
cerebral hemorrhage to prevent a rapid fall in intracranial
pressure

30. Mannitol
•Promotes free-water diuresis by elevating the osmolarity
of the glomerular filtrate
•Used intravenously, as a 15-20% solution.

31. •Demeclocycline
 Induces diabetes insipidus –Impairs generation and
action of cAMP, interfering with the action of AVP on the
collecting duct –Onset of action may take over a week

32. References:
 Harrisons Textbook Of Internal Medicine
 Medscape.com
 Oxford Manual of General Medicine

33. http://crisbertcualteros.page.tl