1. SIADH: Syndrome of inappropriate
anti-diuretic hormone
Hoa-Hong “Waho” Nguyen
2. ADH: Osmoreceptors in the
hypothalamus release ADH in
response to increased
osmolality of plasma (conc of
solutes in blood).
Elevated ADH results in:
● Concentrated urine due to
water retention
● Hyponatremia
3. Pathophysiology: SIADH
A disorder of impaired water excretion caused by the
inability to suppress the secretion of antidiuretic hormone
(ADH). If water intake exceeds the reduced urine output,
the ensuing water retention leads to the development of
hyponatremia. ADH (vasopressin): retain water in body and
constrict blood vessels.
6. Symptoms
● Nausea and vomiting
● Headache
● Confusion or trouble thinking clearly
● Feeling weak or tired
● Feeling restless or irritable
● Muscle weakness, spasms or cramps
● Seizures or passing out
7. Euvolemic Hyponatremia
- ADH (vasopressin)
- increase H2O retention via aquaporin
channels
- no change in sodium
- Reabsorbing water that is free of Na.
8. Euvolemic
ADH ---> increase H20 reabsorption &
volume ---> Natriuretic peptides (increase Na
and H20 excretion) +
Aldosterone (less Na and H2O reabsorbed)
Net effect: Na loss > Water Retention
9. Excess water intake or inappropriate ADH
secretion?
-Measure urine sodium and urine osmolality
-SIADH: urine is usually inappropriately concentrated
(Na greater than 30 mmol/L) and urine osmolality is
usually normal/elevated
-Disorders of excess water intake: urine osmolality less
than 100 mOsm/kg
13. Fluid restriction
-Intake less than 800-1200ml/24 hours in all
presentations...
EXCEPT: Subarachnoid hemorrhage
-Standard
14. Salt Repletion
- When? Severe, symptomatic, or resistant
hyponatremia in patients with SIADH
- Do not use isotonic 0.9% NaCl - worsens
hyponatremia, shifts fluid
- 3% Hypertonic saline solution, 1-2ml/kg IV
over 3-4 hrs
15. Suppose we use 0.9% NaCl...
Initially we will see a rise in serum Na, however, remember that Na handling is intact and there is
generally fixed osmolality...
Case: Patient AB has hyponatremia due to SIADH with a urine cation (Na and K) concentration
300mEq/L (concentrated urine). If we give them 1000ml of isotonic saline (containing 154 mEq Na)
then...
154mEq / X ml isotonic saline = 300mEq / 1000ml
X = 513ml of Isotonic saline is excreted since Na handling is intact (remember only water reabsorption
is affected in SIADH)
1000ml 0.9% NaCl - 513ml that was excreted = 487ml H2O retention in the already hyponatremic
patient, worsening the hyponatremia.
16. 3% NaCl...
Case: Same patient, AB, has hyponatremia due to SIADH with a urine cation
(Na and K) concentration 300mEq/L (concentrated urine). If we give them
1000ml of 3% hypertonic saline (containing 513 mEq each of Na and Cl) then...
513mEq-X / 1000ml 3% saline = 300mEq/1000ml urine
X = 213 mEq remaining
All the water in 3% Nacl being secreted with the 300mEq leaving about
213mEq Na left to distribute in serum.
17. Hypertonic 3% NaCl infusion
Severe hyponatremia
(seizures, coma, obtundation, serum Na+
usually <120
mEq/L, serum Na+
has fallen rapidly over <48h)
● Administer hypertonic (3%) saline at rate of up
to 2-3 mL/kg/h over a few hours or alternatively,
give:
■ initial bolus of 50mL followed by an
additional 200mL over 4-6h
■ initial bolus of 100mL of 3% saline and
repeat bolus 1-2 times at 10min
intervals if symptoms persist
Moderate hyponatremia
(dizziness, confusion, lethargy, serum Na+
<120 mEq/L,
but developing >48h, serum Na+
>120 mEq/L, but
developing <48h)
● Administer hypertonic (3%) saline at rate of
approximately 1 mL/kg/h over several hours
● Adjust infusion to achieve rate of correction of
approximately 6-8 mmol/L per day
● Ensure correction rate <10-12 mEq/L at 24h,
<18 mEq/L at 48h, and <20 at 72h
19. Vasopressin Receptor Antagonist
- Less water absorption
- Conivaptan ( IV only, V1 and V2 receptors)
and Tolvaptan, Satavaptan*, Lixivaptan* (PO
only, V2 receptor)
- Selective water diuresis, no effect on Na and
K
*Not available in USA*
20. Drug Tolvaptan Conivaptan
Indication Euvolemic/hypervolemic
hyponatremia associated with
heart failure or SIADH
Euvolemic and hypervolemic
hyponatremia in hospitalized patients
Dose Oral, Initial: 15mg once daily;
after at least 24 hours, may
increase to 30mg once daily to a
maximum of 60 mg once daily
titrating at 24-hour intervals to
desired serum sodium
concentration. *Can also crush
and use in NG tube*
IV LD: 20 mg over 30 mins as a
loading dose, followed by 20mg/24
hours (0.83 mg/hour) for 2-4 days; max
dose of 40mg/24 hours (1.7 mg/hour) if
serum sodium not rising sufficiently;
total duration of therapy not to exceed
4 days. *Central line*
Renal
Dose
Not recommended CrCl <10
mL/minute
Not recommended CrCl < 30ml/min
21. Drug Tolvaptan Conivaptan
Hepatic
Dose
Avoid with underlying liver
disease/cirrhosis.
Do not use for more than 30 days due to
the risk of hepatotoxicity
Moderate impairment: IV LD: 10mg/30 mins,
followed 10mg/24 hours (0.42 mg/hour) for 2-4
days; max dose of 20mg/24 hours (0.83
mg/hour) if serum sodium not rising sufficiently;
total duration of therapy not to exceed 4 days.
Not studied in severe hepatic impairment.
CI Hypovolemic hyponatremia, urgent need
to raise serum sodium acutely, use in
patients unable to sense or appropriately
respond to thirst, concurrent use with
strong CYP3A inhibitors, anuria,
Hypersensitivity/allergy to corn or corn
products, use in hypovolemic hyponatremia;
concurrent use with strong CYP3A4 inhibitors,
anuria
Monitor [Na], rate [Na] increase, neurological
status, [K] (if >5 mEq/L prior to
administration or receiving medications
known to elevate K), volume status,
hepatotoxicity
Rate [Na] increase, neurological status, BP,
volume status, urine output
22. Vasopressin Receptor Antagonists: Thirst
- Will make the patient more thirsty, let patient
know to drink only when needed when using
Conivaptan
- However, they can drink more freely in
Tolvaptan
23. Tolvaptan in Heart Failure
-Increase ADH associated increasing severity of HF -
increased congestion, hyponatremia increased mortality
association
- ACTIV trial (Acute and chronic therapeutic impact of a
vasopressin antagonist in CHF)
- Found that tolvaptan significantly increased urine output
and decreased body weight - improved clinical status of
patients (no mortality benefit) compared to the non-selective
vaptan
24. Tolvaptan in patients with SIADH
and small cell lung cancer
- SIADH occurs in 10-15% of patients with
SCLC
- Use when standard hyponatremia treatment
such as fluid restriction +/- 3% Nacl fails
- Potential to improve prognosis, shorten
inpatient treatment periods
25. Reset Osmostat
- Suspect when mild hyponatremia that is stable over several days
despite variations in Na and H2O intake
- Test response to water load
- Give 10-15ml/kg H2O PO/IV, those with reset osmostat should
excrete more than 80% of the water load within 4 hours while
excretion will be impaired in SIADH)
- If believe osmostat has been reset, treating underlying disease is
main focus. Does not require correction since usually asymptomatic
and steady serum Na (often mild/moderate hyponatremia).
26. Other treatment options
-Oral salt intake +/- loop diuretic
-Urea (effective, but not readily available in
USA)
-Demeclocycline and lithium (diminish response
of CD to ADH) - however both are nephrotoxic
and have more severe side effects, takes
longer to produce rise [Na]
27. Central pontine myelinolysis: Rate of
[Na] Correction
Androgue-Madias formula: change in serum [Na] that can be expected from a
saline infusion
Central pontine myelinolysis (osmotic demyelination syndrome) - occurs when
rate of correction is too high
*Rate of correction < 12 mmol/liter/day critical for prevention*
28. References
1. Soupart A, Coffernils M, Couturier B, et al. Efficacy and tolerance of urea compared with vaptans for long-term treatment of patients with SIADH. Clin
J Am Soc Nephrol. 2012;7:742-47.
2. Petereit C, Zaba O, Teber I, et al. A rapid and efficient way to manage hyponatremia in patients with SIADH and small cell lung cancer: treatment with
tolvaptan. BMC Pulm Med. 2012;13.
3. Lee JJY, Kilonza K, Nisico A, et al. Management of hyponatremia. CMAJ. 2014;186:E281-286.
4. Yasukatsu I, Katsuyuki M, Hiroshi I. Therapeutic potential of vasopressin-receptor antagonists in heart failure. J Pharmacol Sci. 2014;124:1-6.
5. Sterns RH. UpToDate. Wolters Kluwer Health; 2014. http://www.uptodate.com/contents/treatment-of-hyponatremia-syndrome-of-inappropriate-
antidiuretic-hormone-secretion-siadh-and-reset-osmostat?source=search_result&search=siadh&selectedTitle=2~150#H3 . Accessed 6 July 2015.
6. Sterns RH. UpToDate. Wolters Kluwer Health; 2015. http://www.uptodate.com/contents/overview-of-the-treatment-of-hyponatremia-in-adults?
source=see_link§ionName=Do+not+use+isotonic+saline+in+SIADH&anchor=H780040#H780040. Accessed 6 July 2015.
7. Sterns RH, Gottlieb SS. UpToDate. Wolters Kluwer Health; 2014. http://www.uptodate.com/contents/hyponatremia-in-patients-with-heart-failure?
source=search_result&search=Conivaptan&selectedTitle=5~15. Accessed 6 July 2015.
8. Sterns RH. UpToDate. Wolters Kluwer Health; 2013 2015.http://www.uptodate.com/contents/osmotic-demyelination-syndrome-and-overly-rapid-
correction-of-hyponatremia?source=see_link. Accessed 6 July 2015.
9. Beltran J, Bohdan M, Briner E, et al. Clin-Eguide. Ovid; 2014. http://clinicalresource.ovid.com/clinicalresource/re/displayCG?
accessionPath=mdcgebdb/2798&dbName=mdcgeb&title=5489793&actionIndex=3&fileName=/CG_12577-32_381/root[1]&tocFileName=/CG_12577-
0_381/root[1]. Accessed 6 July 2015.
10. Gross P. Clinical management of SIADH. Ther Adv Endocrinol Metab. 2012;3:61-73.
