ABSTRACT
BACKGROUND: Hyponatremia is common among hospital inpatients. It is generally due to excess free body water resulting from increased water intake and decreased water elimination due to underlying pathology and hormonal influence. However, supporting evidence is lacking for treating mild hyponatremia with fluid restriction. Our study examines the association between hyponatremia and fluid intake in acutely ill inpatients. We hypothesize that fluid intake is not closely associated with serum sodium (SNa). METHODS: We conducted a retrospective study of hyponatremia using the Multiparameter Intelligent Monitoring in Intensive Care (MIMIC) III dataset, a public ICU registry. We analyzed fluid, sodium, and potassium intake with a mixed model linear regression with SNa as the outcome for hyponatremic and non-hyponatremic patients and cumulative total input from one to seven days. In addition, we compared a group of patients receiving less than one liter of fluid per day to a group receiving more than one liter. RESULTS: The association of SNa with fluid intake was negative and statistically significant for most cumulative days of intake from one to seven for the total population and those with sporadic hyponatremia. For those with uniform hyponatremia, the negative association was significant for three and four days of cumulative input. The change in SNa was almost always less than 1 mmol/L of additional fluid intake across all groups. SNa for hyponatremic patients who received less than one liter of fluid per day were within one mmol/L of those who received more (p<0.001 for one, two, and seven cumulative intake days). CONCLUSIONS: SNa is associated with a change of less than 1 mmol/L across a wide range of fluid and sodium intake in adult ICU patients. Patients who received less than one liter per day had SNa almost identical to those who received more. This suggests that SNa is not tightly coupled with fluid intake in the acutely ill population and that hormonal control of water elimination is the predominant mechanism. This might explain why the correction of hyponatremia by fluid restriction is often difficult.
ABSTRACT
INTRODUCTION: To date, there is no FDA-approved treatment for agitation in Alzheimer's disease (AD). Medications currently used off-label have modest clinical efficacy and serious side effects. AREAS COVERED: The authors review the pharmacology, mechanism of action, pharmacokinetics, efficacy, safety and tolerability data of AVP-786, for the treatment of agitation in AD. EXPERT OPINION: AVP-786, the deuterated form of dextromethorphan/quinidine (AVP-923) which is an approved treatment for Pseudo-Bulbar Affect, emerges as a promising and safe treatment for agitation in AD. Deuteration is an innovative technology that accelerates drug development by conducting faster and less costly clinical trials. No phase II trial was conducted with AVP-786 for the treatment of agitation in AD; the decision to expedite the development of this drug was based on a successful phase II study with AVP-923. Phase III trials with AVP-786 (TRIAD-1 and TRIAD-2) showed mixed findings probably due to the difference in study design. Future phase III studies should use innovative study designs such as the Sequential Parallel Comparison Design to mitigate high placebo response, and the Cohen-Mansfield Agitation Inventory for agitation assessment. They should also include positron emission tomography studies to assess occupancy of various receptors in the brain after AVP-786 is administered.
