Abstract
Introduction
Hyponatremia is the most common electrolyte imbalance caused by serum sodium level of less than 135mmol/L, prevailing 15 and 30% among hospitalised patients [Zhang X, Li XY. Eur Geriatr Med. 2020;11(4):685-692]
Methods
PRISMA guidelines were followed for this study. Pubmed was searched with the search term : (hyponatremia) AND (treatment OR control OR management[MeSH]) AND (elderly[MeSH]) with filters, timeline: 2000 to 21/07/2023, free full text articles and human species.Data extraction was done using Covidence app and depicted in PRISMA Flow diagram. Quality assessment was done by Cochrane Risk of Bias version 1.Odd’s ratio with 95% conifidence interval was calculated for dichotomous outcomes. Mantel-Haenszel statistical method along with random effects model was used. Cochrane Q test was employed and I2 index was computed. Forest and Funnel plots were plotted. The analysis was done by Cochrane Review Manager.
Results
Out of 3222 results , 9 studies were included with total 980 patients. 8 were of vaptans and 1 of empagliflozin. Of the vaptans, tolvaptan was studied in 5 studies, satavaptan, lixivaptan and conivaptan in other three. Three studies had low risk of bias and were included in meta-analysis.Mean age and BMI were 70.55(SD=14.5) years and 24.73(SD=3.95) kg/m2 respectively.
Most frequently occuring etiology , comorbidity and symptom were congestive heart failure, hypertension and fatigue/malaise respectively. Mean baseline serum sodium was 124.89 mmol/L mean rise was 9.142 mmol/L.
Meta-analysis showed that placebo was significantly associated with achieving normonatremia as compared to treatment group(OR=2.5, 95%CI:1.54,4.04, p=0.0002,I2=0%).
The most frequent reported side effects were nausea, dry mouth, pyrexia and thirst.Side effects both mild/moderate (OR=1.12, 95%CI:0.69,1.81, p=0.65, I2 =0%) and serious (OR= 1.51, 95%CI: 0.77,2.98, p=0.23,I2 =0%) showed no difference between treatment and placebo groups.
Treatment was not associated with rapid risk of overcorrection (OR=1.65, 95% CI:0.57,4.81, p=0.36, I2 =0%). None showed osmotic demyelination syndrome.
Discussion
The main conclusions drawn out were:
(1) The most commonly available drugs beside fluid restriction, hypertonic saline were vaptans- vasopressin receptor 2 antagonists.
(2) The possible new drug of choice for treatment of Hyponatremia could be empagliflozin.
Meta-analysis carried out for three studies [28, 29, 34] showed no significant improvement in Hyponatremia by treatment with hyponatremia drugs i.e., satvaptan, lixivaptan and empagliflozin as compared to placebo.
Instead placebo reported a significant improvement Hyponatremia.These results were similar to a review by Jovanovich [37] et al which concluded that they have no role in treatment.
Currently only tolvaptan and conivaptan are approved by the FDA for treatment of hypervolemic and euvolemic hyponatremia The use of vasopressin receptor antagonists remains limited due to its controversial efficacy and potential risks for overcorrection [9].
Rapidly correcting hyponatremia (>12 mEq/L/24 hours) can cause osmotic demyelination, leading to dysarthria, mutism, dysphagia, lethargy, emotional abnormalities, spastic quadriparesis, seizures, coma, and death.
We did not find any significant rapid overcorrection of Hyponatremia in treatment group as compared to placebo. This was in contrast to Krisapan et al[38]which reported a greater risk of rapid overcorrection. This could be due to small sample size of the study and yet 3 studies in this review (Estilo et al, Humayun et al and Sag et al) recommended starting with a small dose and imply strict sodium monitoring and for those with a history of hyperlipidemia and who have recently taken thiazide diuretics.
No significant association of treatment group was found with mild/moderate/severe side effects.
Refardt et al showed that empagliflozin could be a promising new treatment due to its reported long term cardiovascular and nephroprotective effects, broader availability and good tolerability. With the daily treatment cost of empagliflozin being similar to urea(2USD vs 4USD), it was th cost of Tolvaptan and therefore it could prove a cost effective treatment option in future when fluid restriction and hypertonic saline fail [37,39].
Conclusion
We conclude that vaptans and Empagliflozin ,although safe, show limited efficacy in hyponatremia treatment.