Hyponatremia: The Optimal Way to Make Your Patient Saltier
CASE
History
80 yo M with a PMHx of bladder, prostate, and pharyngeal cancer with metastases to the liver and lungs, DVT, TIA with no residual deficits, atrial fibrillation on Eliquis, and b/l retinal detachments (repaired) who was referred to the ED by his PCP for a sodium level of 120.
Patient has been hyponatremic for the last week, and his PCP managed the patient’s hyponatremia with fluid restriction and salt tablets (1 gram three times a day). Patient’s mental status and processing speed has steadily declined over the last few days, despite fluid restriction and use of salt tablets.
ROS notable for chest tightness, dyspnea on exertion, orthopnea, productive cough, lower extremity swelling, and presyncope.
Negative for syncope, trauma, fever, headache, chills, nausea, vomiting, abdominal pain, diarrhea, constipation, dysuria, or hematuria.
Physical Exam
Vitals on arrival: BP 141/90, P 83, RR 17, T 97.7F, O2 Sat 98% on RA.
General: Not in acute distress. Normal appearance. Not ill-appearing, toxic, or diaphoretic.
Neurological: A&Ox3 (best: A&Ox4) (not oriented to time, though relative states this is his baseline); no focal deficits; no cranial nerve, strength, or sensory deficits.
HEENT: normocephalic, atraumatic, EOM intact, PERRLA.
Cardiovascular: irregular rhythm without murmurs, rubs, or gallops; 2+ radial and pedal pulses.
Pulmonary: pulmonary effort normal; no respiratory distress; decreased breath sounds at bases bilaterally; no stridor; no wheezing.
Abdominal: mild distension; soft, nontender; no guarding, rebound; no CVA tenderness.
Musculoskeletal: normal ROM in all extremities; 2+ edema in RLE and LLE.-
ED Management
CMP notable for sodium 120 mmol/L (normal: 135-145 mmol/L)
Whole blood sodium – 120 mmol/L (normal: 135-145 mmol/L)
Serum osmolality – 249 mOsm/kg (normal: 275-295 mOsm/kg)
EKG – atrial fibrillation at 77 bpm; no ST segment abnormalities
CXR – increasing interstitial opacities noted with trace pleural effusions and pulmonary venous congestion, likely pulmonary interstitial edema
Hyponatremia managed via fluid restriction, salt tablets, and serial sodium level checks.
Admitted for hypervolemic hyponatremia likely secondary to SIADH in the setting of the patient’s malignancies. Presence of orthopnea and lower extremity edema suggest a component of heart failure related etiology. Pending urine osmolality and urine sodium.
Clinical Question: Are there differences in clinical outcomes, morbidity rates, or mortality rates based on the clinical strategy chosen to correct symptomatic hyponatremia?
SUMMARY OF EVIDENCE
Baek et. al. (2021) performed the SALSA randomized clinical trial (n = 178 patients) to compare the risk of overcorrection in rapid intermittent bolus (RIB) and slow continuous infusion (SCI) with hypertonic saline in patients with symptomatic hyponatremia.
Inclusion criteria: older than 18 years with moderate (nausea, headache, drowsiness, general weakness, and malaise) to severe (vomiting, stupor, seizure, and coma) hyponatremia and glucose-corrected serum sodium levels of 125 mmol/L or less.
Exclusion criteria: primary polydipsia (urine osmolality ≤100 mOsm/kg), pregnant, breastfeeding, anuric, arterial hypotension (systolic blood pressure <90 mm Hg and MAP <70 mm Hg), liver disease, uncontrolled diabetes mellitus (A1C >9%), history of cardiac surgery, acute myocardial infarction, sustained ventricular tachycardia, ventricular fibrillation, acute coronary syndrome, cerebral trauma, and increased intracranial pressure within 3 months prior to randomization.
Overcorrection occurred in 15 of 87 (17.2%) patients in the RIB group and 22 of 91 (24.2%) patients in the SCI group (p=0.26).
RIB group showed lower incidence of requiring relowering treatment than the SCI group (p=0.04).
Groups did not differ in terms of efficacy in increasing sodium concentrations nor improving symptoms, but RIB showed better efficacy in achieving target correction rate within 1 hour than SCI (p=0.02).
Locket et. al. (2019) performed a retrospective study to evaluate the safety and efficacy of urea as a treatment for fluid restriction-refractory hyponatremia.
Inclusion criteria: inpatients with moderate hyponatremia (serum sodium < 130 mg/dL) treated with urea and inpatients with SIADH treated with fluid restriction alone.
Exclusion criteria: age <18 years, pregnancy, and pseudohyponatremia due to hyperglycemia or hyperlipidemia.
The urea (n = 78) and fluid restriction (n = 51) group did not differ in proportion of individuals with Na ≥ 130 mg/dL, days until Na ≥ 130 mg/dL, or days until Na ≥ 135 mg/dL (p > 0.05).
The starting dose of urea correlated significantly with the subsequent change in serum sodium (r = 0.291, P = 0.012) with 30 g daily being the minimum needed to achieve a serum sodium ≥ 135 mg/dL within 72 hours.
Seventeen patients (21.8%) had side effects, distaste the most common (7), followed by nausea (6) and hypokalemia (4). None developed hypernatremia, overcorrection, osmotic demyelination or died.
RECOMMENDATIONS
A paucity of RCTs exist that investigate the differences in clinical outcomes, morbidity rates, or mortality rates for the management of hyponatremic patients.
Though both safe and effective with no difference in overcorrection risk, rapid intermittent bolus is preferred over slow continuous infusion of hypertonic saline due to the lower incidence of needing therapeutic relowering treatment and the tendency to have better efficacy in achieving goal serum sodium within 1 hour.
Similarly, there is a growing body of evidence that urea can be used as a safe, effective, and well-tolerated treatment for hyponatremia, especially for patients who are unable to undergo or have failed fluid restriction.
REFERENCES
1. Halawa, Imad, Tomas Andersson, and Torbjörn Tomson. "Hyponatremia and risk of seizures: a retrospective cross‐sectional study." Epilepsia 52.2 (2011): 410-413
2. Lockett, Jack, et al. "Urea treatment in fluid restriction‐refractory hyponatraemia." Clinical endocrinology 90.4 (2019): 630-636
3. Baek, Seon Ha, et al. "Risk of overcorrection in rapid intermittent bolus vs slow continuous infusion therapies of hypertonic saline for patients with symptomatic hyponatremia: the SALSA randomized clinical trial." JAMA internal medicine181.1 (2021): 81-92
4. Chawla, Arun, et al. "Mortality and serum sodium: do patients die from or with hyponatremia?." Clinical Journal of the American Society of Nephrology 6.5 (2011): 960-965
5. Lee, Jennifer Ji Young, et al. "Management of hyponatremia." CMAJ 186.8 (2014): E281-E286.
6. Sterns, Richard H. "Treatment of severe hyponatremia." Clinical Journal of the American Society of Nephrology 13.4 (2018): 641-649
7. Winzeler, Bettina, et al. "Long-term outcome of profound hyponatremia: a prospective 12 months follow-up study." Eur J Endocrinol 175.6 (2016): 499-507
8. Rondon-Berrios, Helbert, et al. "Urea for the treatment of hyponatremia." Clinical journal of the American Society of Nephrology: CJASN 13.11 (2018): 1627
Weerakkody Y, Anan R, Jabaz D, et al. “Pulmonary edema.” Reference article, Radiopaedia.org (Accessed on 10 Jan 2023) https://doi.org/10.53347/rID-16256
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