Study design and participants
This single-center, open-label, randomized controlled trial was conducted at Bhumibol Adulyadej Hospital. The study protocol was approved by the Institutional Review Board of Bhumibol Adulyadej Hospital and was registered in the Thai Clinical Trials Registry (TCTR). This study was conducted in accordance with the ethical principles of the 1964 Declaration of Helsinki and its later amendments. The investigators informed patients or their surrogates concerning the study orally and written informed consent was given before entry into the study.
Eligible participants were adults aged ≥ 18 years with laboratory-confirmed serum sodium < 125 mmol/L and severe symptoms including nausea, vomiting, and changes in consciousness (such as seizures, drowsiness, and coma). Exclusion criteria included hypotension (systolic blood pressure < 90 mmHg and mean arterial pressure < 65 mmHg), anuria (daily urine output < 100 ml), advanced stage chronic kidney disease (glomerular filtration rate estimated by Chronic Kidney Epidemiology Collaboration [CKD-EPI] equation < 30 ml/min/1.73 m2), volume overload (e.g., decompensated liver cirrhosis, congestive heart failure), current use of desmopressin, bleeding disorders, pregnancy or breastfeeding, history of the following included cardiac surgery, sustained ventricular tachycardia, ventricular fibrillation, myocardial infarction, traumatic brain injury, increased intracranial pressure within 3 months, and allergic reaction to desmopressin.
Procedures
The patients were randomly assigned in a 1:1 ratio to receive either proactive or reactive DDAVP strategies in conjunction with 3%NaCl. The allocation sequence used computer-generated random numbers in a block of fours and allocation concealment. Serum sodium levels were determined through an indirect ion-selective electrode (ISE) method. All patients underwent laboratory tests to assess serum osmolality, blood urea nitrogen (BUN), serum creatinine (Cr), urine osmolality, and urine sodium levels before starting an intravenous drip of 2 ml/kg (maximum 150 ml per dose) of 3%NaCl over 20 min. To ensure the study focused on true hyponatremia, cases of isotonic or hypertonic hyponatremia, such as those induced by hyperglycemia, were excluded. The proactive group received early DDAVP in conjunction with 3%NaCl after the initial serum sodium level was reported and before subsequent serum sodium measurements were taken. The reactive group utilized DDAVP when serum sodium levels tended to increase beyond the limited range. Specifically, DDAVP was administered for a serum sodium rise of 7–8 mmol/L within the first 24 h or 15–16 mmol/L within 48 h, or a 7–8 mmol/L increase from the 24-h to the 48-h period for patients at high risk of ODS—characterized by initial serum sodium < 105 mmol/L, hypokalemia, malnutrition, advanced liver disease, and alcoholism. For those at low risk of ODS—defined as individuals without these high-risk conditions—DDAVP was administered for a serum sodium increase of 9–10 mmol/L within the first 24 h or 17–18 mmol/L within 48 h, or an increase of 7–8 mmol/L from the 24-h to the 48-h period.
Following the initial differential use of DDAVP, both groups were managed with standard hyponatremia care, involving the investigation and treatment of underlying causes, administration of intravenous hypertonic saline, and administration and repeated doses of intravenous DDAVP at 2 mcg every 6 to 8 h as required. If overcorrection occurred, patients were managed with a rescue strategy. Data collection covered baseline characteristics, clinical data, and serum sodium levels measured at 1, 6, 24, and 48 h post-initial treatment. Although serum sodium was specifically collected at these times, monitoring occurred more frequently at 1, 6, 12, 18, 24, 30, 36, 42, and 48 h. We also recorded urine output, the volume of intravenous fluids administered, and DDAVP dosages. Furthermore, the incidence of ODS and the 28-day mortality rate were assessed. The research protocol is shown in Fig. 1.
Research protocol. NaCl, sodium chloride; ml/kg, milliliter/kilogram; S Na, serum sodium, DDAVP, Desmopressin or 1-deamino 8-d-arginine vasopressin; DW, dextrose in water; ODS, osmotic demyelination syndrome.
Outcomes
The primary outcome was the incidence of overcorrection between proactive and reactive strategies for the treatment of severe symptomatic hyponatremia. Overcorrection was defined as a serum sodium increase > 10 mmol/L in the first 24 h or > 18 mmol/L in any 48 h in low-risk ODS patients, and > 8 mmol/L in any 24 h in patients at high risk of ODS.
The secondary outcomes included the changes in serum sodium levels at 1, 6, 24, and 48 h after 3%NaCl administration, time to symptom improvement, the total amount of intravenous fluid administered, hospital length of stay, total urine volume, and safety outcomes. The safety outcomes encompassed the percentage of patients requiring relowering treatment, the incidence of ODS—diagnosed through clinical observation of neurological changes, with MRI of the brain performed for confirmation in suspected cases—and the 28-day mortality rate. These measures aimed to compare the safety and efficacy of proactive and reactive strategies in managing severe symptomatic hyponatremia.
Statistical analysis
Assuming a proportion of participants experiencing overcorrection based on previous literature13,16,21, we determined that a sample size of 66 participants would yield 80% statistical power to detect a significant difference in the incidence of overcorrection between the proactive and reactive groups, employing an alpha (ɑ) level of 0.05, beta (ꞵ) of 0.2, and accounting for a 10% dropout rate. For statistical analysis, continuous data were summarized as means ± SD or medians with IQR, contingent on data distribution, and compared using appropriate tests such as the Student t-test or Wilcoxon Rank Sum test. Categorical data were presented as frequencies and percentages and assessed using the Chi-squared test or Fisher’s exact test when appropriate. Results were considered statistically significant when the p-value was ≤ 0.05 for all tests. Data analysis was conducted utilizing R version 4.2.1.
Ethical approval
The study was approved by the Institutional Review Board of Bhumibol Adulyadej Hospital and was registered in the Thai Clinical Trials Registry (TCTR) with the registration number TCTR20221105001. Informed, written consent was provided by all participants or their surrogates before trial commencement.
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- Source: https://www.nature.com/articles/s41598-024-57657-z