Page 29 - Read Online

Khan et al. J Cancer Metastasis Treat 2019;5:71 I http://dx.doi.org/10.20517/2394-4722.2019.017 Page 9 of 12

CENTRAL PONTINE MYELINOLYSIS
The rapid correction of hyponatremia by any means can cause central pontine myelinolysis, also known
[36]
as osmotic demyelination syndrome . It is characterized by severe and often irreversible neurologic
sequelae such as dysarthria, dysphagia, psychiatric disturbances, spastic paraplegia or quadriplegia, seizures,
pseudobulbar palsy, and altered mental status. Symptoms of osmotic demyelination occur 4-6 days after
[37]
rapid overcorrection . Therefore, the overall goal of treatment should be to avoid increasing the serum sodium
levels by more than 0.5 mEq/L/h (or 10 mEq/L/day) and 8 mEq per subsequent day [10,38] . However, some experts
recommend an even more conservative therapeutic goal of an increase of no more than 8 mEq/day [33,39] . Serum
sodium levels should be assessed every 2-4 h during the initial stages of treatment for severe symptomatic
hyponatremia. Desmopressin, 1-2 μg parenterally every 6-8 h, has been used along with hypertonic saline to
reduce the risk of rapid correction, although further studies are needed to confirm the effectiveness of this
[40]
approach . In addition to the degree of hyponatremia and rate of hyponatremia development, factors that
also increase the risk of osmotic demyelination syndrome include liver disease, concurrent use of thiazide
diuretics, and antidepressants. Suppression of AVP release with volume repletion in patients with reduced
extracellular volume increases the risk of rapid correction of sodium due to increase free water clearance.
[10]
In addition to close monitoring of urine output, serum sodium should be monitored every 2 h .

VAPTANS: MECHANISM OF ACTION, CLINICAL IMPLICATIONS AND FUTURE PERSPECTIVES
Vaptans are AVP receptor antagonists that are FDA-approved for clinical use in patients with euvolemic
and hypervolemic hyponatremia. AVP antagonists block vasopressin receptors on principal cells in the
renal collecting tubules. Inhibition of AVP receptors blocks increase in cAMP and protein kinase A that
leads to reduced translocation of aquaporin 2 (water channels) to the luminal membrane. Binding of
vaptans decreases the permeability of the apical membrane to water. Vaptans are aquaretic agents because
[13]
they enhance electrolyte free-water clearance without associated natriuresis . Vaptans are utilized to
reduce fluid restriction in patients with symptomatic mild to moderate chronic hyponatremia due to SIAD
[39]
and heart failure . Conivaptan is a non-peptide dual V1A/V2 AVP receptor antagonist. Conivaptan,
given as an initial i.v. bolus followed by a continuous infusion, increases serum sodium up to 6 mEq/L as
compared with placebo. Use of i.v. conivaptan can be associated with rapid correction of hyponatremia,
transient symptomatic hypotension, and peripheral i.v. site reaction. Patients receiving conivaptan
[41]
through a central venous catheter did not have any adverse reactions . The most common reason for
[42]
discontinuation of conivaptan is infusion site reaction . Tolvaptan is an oral V2-receptor antagonist also
approved for use in euvolemic or hypervolemic hyponatremia. The most common adverse effects reported
during tolvaptan use are thirst and dry mouth. Although it is an oral medication, the use of tolvaptan
should be limited to the inpatient setting to monitor for overcorrection of serum sodium following
administration.

Vaptan use has been associated with alanine aminotransferase elevation and hepatotoxicity with long term
use. During treatment with vaptans, in addition to close monitoring of serum sodium, urine osmolality
should be monitored. The dose of vaptan should be increased if the urine osmolality remains high. If
[13]
urine osmolality is low, fluid intake should be restricted . The clinical trials evaluating these agents did
[43]
not include patients with serum sodium less than 115 mEq/L . Caution is advised in patients with acute
[39]
symptomatic hyponatremia, underlying liver disease, and volume depletion . Post hoc analysis from the
trial ACTIVE showed a reduction in mortality ~50% in patients with congestive heart failure after the
correction of hyponatremia with the use of tolvaptan. The EVERST trial evaluated the role of tolvaptan
(30 mg Po QD) in cardiac failure patients for 2 years. There was no difference in all cause mortality in
[41]
tolvaptan treated patients versus placebo .
In the SALT WATER trial, long term use of tolvaptan (2 years) was evaluated for safety and efficacy in
patients with euvolemic and hypervolemic hyponatremia. Hypernatremia was reported in only one patient.