Treatment Guidelines for Hyponatremia: Stay the Course.

International guidelines designed to minimize the risk of complications that can occur when correcting severe hyponatremia have been widely accepted for a decade. On the basis of the results of a recent large retrospective study of patients hospitalized with hyponatremia, it has been suggested that hyponatremia guidelines have gone too far in limiting the rate of rise of the serum sodium concentration; the need for therapeutic caution and frequent monitoring of the serum sodium concentration has been questioned. These assertions are reminiscent of a controversy that began many years ago. After reviewing the history of that controversy, the evidence supporting the guidelines, and the validity of data challenging them, we conclude that current safeguards should not be abandoned. To do so would be akin to discarding your umbrella because you remained dry in a rainstorm. The authors of this review, who represent 20 medical centers in nine countries, have all contributed significantly to the literature on the subject. We urge clinicians to continue to treat severe hyponatremia cautiously and to wait for better evidence before adopting less stringent therapeutic limits.

Estimating urine volume from the urine creatinine concentration.

Spot determinations of the urine creatinine concentration are widely used as a substitute for 24-h urine collections. Expressed as the amount excreted per gram of creatinine, urine concentrations in a single-voided sample are often used to estimate 24-h excretion rates of protein, sodium, potassium, calcium, magnesium, urea and uric acid. These estimates are predicated on the assumption that daily creatinine excretion equals 1 g (and that a urine creatinine concentration of 100 mg/dL reflects a 1 L 24-h urine volume). Such estimates are invalid if the serum creatinine concentration is rising or falling. In addition, because creatinine excretion is determined by muscle mass, the assumption that 24-h urine creatinine excretion equals 1 g yields a misleading estimate at the extremes of age and body size. In this review, we evaluate seven equations for the accuracy of their estimates of urine volume based on urine creatinine concentrations in actual and idealized patients. None of the equations works well in patients who are morbidly obese or in patients with markedly decreased muscle mass. In other patients, estimates based on a reformulation of the Cockroft-Gault equation are reasonably accurate. A recent study based on this relationship found a high strength of correlation between estimated and measured urine output with chronic kidney disease (CKD) studied in the African American Study of Kidney Disease (AASK) trial and for the patients studied in the CKD Optimal Management with Binders and NictomidE (COMBINE) trial. However, the equation systematically underestimated urine output in the AASK trial. Hence, an intercept was added to account for the bias in the estimated output. A more rigorous equation derived from an ambulatory Swiss population, which includes body mass index and models the non-linear accelerated decline in creatinine excretion with age, could potentially be more accurate in overweight and elderly patients. In addition to extremes of body weight and muscle mass, decreased dietary intake or reduced hepatic synthesis of creatine, a precursor of creatinine or ingestion of creatine supplements will also result in inaccurate estimates. These limitations must be appreciated to rationally use predictive equations to estimate urine volume. If the baseline urine creatinine concentration is determined in a sample of known volume, subsequent urine creatinine concentrations will reveal actual urine output as well as the change in urine output. Given the constraints of the various estimating equations, a single baseline timed collection may be a more useful strategy for monitoring urine volume than entering anthropomorphic data into a calculator.

Hypertonic Saline for Hyponatremia: Meeting Goals and Avoiding Harm.

Hypertonic saline has been used for the treatment of hyponatremia for nearly a century. There is now general consensus that hypertonic saline should be used in patients with hyponatremia associated with moderate or severe symptoms to prevent neurological complications. However, much less agreement exists among experts regarding other aspects of its use. Should hypertonic saline be administered as a bolus injection or continuous infusion? What is the appropriate dose? Is a central venous line necessary? Should desmopressin be used concomitantly and for how long? This article considers these important questions, briefly explores the historical origins of hypertonic saline use for hyponatremia, and reviews recent evidence behind its indications, dosing, administration modality and route, combined use with desmopressin to prevent rapid correction of serum sodium, and other considerations such as the need and degree for fluid restriction. The authors conclude by offering some practical recommendations for the use of hypertonic saline.

Fatal case of hospital-acquired hypernatraemia in a neonate: lessons learned from a tragic error.

A 3-week-old boy with viral gastroenteritis was by error given 200 mL 1 mmol/mL hypertonic saline intravenously instead of isotonic saline. His plasma sodium concentration (PNa) increased from 136 to 206 mmol/L. Extreme brain shrinkage and universal hypoperfusion despite arterial hypertension resulted. Treatment with glucose infusion induced severe hyperglycaemia. Acute haemodialysis decreased the PNa to 160 mmol/L with an episode of hypoperfusion. The infant developed intractable seizures, severe brain injury on magnetic resonance imaging and died. The most important lesson is to avoid recurrence of this tragic error. The case is unique because a known amount of sodium was given intravenously to a well-monitored infant. Therefore the findings give us valuable data on the effect of fluid shifts on the PNa, the circulation and the brain's response to salt intoxication and the role of dialysis in managing it. The acute salt intoxication increased PNa to a level predicted by the Edelman equation with no evidence of osmotic inactivation of sodium. Treatment with glucose in water caused severe hypervolaemia and hyperglycaemia; the resulting increase in urine volume exacerbated hypernatraemia despite the high urine sodium concentration, because electrolyte-free water clearance was positive. When applying dialysis, caution regarding circulatory instability is imperative and a treatment algorithm is proposed.

Osmotic Demyelination Syndrome following Correction of Hyponatremia by ≤10 mEq/L per Day.

Background: Overly rapid correction of chronic hyponatremia may lead to osmotic demyelination syndrome. European guidelines recommend a correction to ≤10 mEq/L in 24 hours to prevent this complication. However, osmotic demyelination syndrome may occur despite adherence to these guidelines. Methods: We searched the literature for reports of osmotic demyelination syndrome with rates of correction of hyponatremia ≤10 mEq/L in 24 hours. The reports were reviewed to identify specific risk factors for this complication. Results: We identified 19 publications with a total of 21 patients that were included in our analysis. The mean age was 52 years, of which 67% were male. All of the patients had community-acquired chronic hyponatremia. Twelve patients had an initial serum sodium <115 mEq/L, of which seven had an initial serum sodium ≤105 mEq/L. Other risk factors identified included alcohol use disorder (n=11), hypokalemia (n=5), liver disease (n=6), and malnutrition (n=11). The maximum rate of correction in patients with serum sodium <115 mEq/L was at least 8 mEq/L in all but one patient. In contrast, correction was <8 mEq/L in all but two patients with serum sodium ≥115 mEq/L. Among the latter group, osmotic demyelination syndrome developed before hospital admission or was unrelated to hyponatremia overcorrection. Four patients died (19%), five had full recovery (24%), and nine (42%) had varying degrees of residual neurologic deficits. Conclusion: Osmotic demyelination syndrome can occur in patients with chronic hyponatremia with a serum sodium <115 mEq/L, despite rates of serum sodium correction ≤10 mEq/L in 24 hours. In patients with severe hyponatremia and high-risk features, especially those with serum sodium <115 mEq/L, we recommend limiting serum sodium correction to <8 mEq/L. Thiamine supplementation is advisable for any patient with hyponatremia whose dietary intake has been poor.

Adverse Consequences of Overly-Rapid Correction of Hyponatremia.

A time-dependent loss of cell solute protects against lethal cerebral edema in hyponatremia. This adaptation, which makes survival possible when the serum sodium concentration is extremely low, also makes the brain vulnerable to injury if chronic (>48 hours) hyponatremia is corrected more rapidly than lost brain solutes can be recovered. Rapid correction of chronic hyponatremia results in programmed cell death of astrocytes and oligodendrocytes and presents clinically with a delayed onset of neurological findings, known as the osmotic demyelination syndrome. This iatrogenic complication can be avoided by limiting correction of hyponatremia to <8 mEq/L per day.

Allostasis and the Clinical Manifestations of Mild to Moderate Chronic Hyponatremia: No Good Adaptation Goes Unpunished.

When homeostatic regulatory systems are unable to maintain a normal serum sodium concentration, the organism must adapt to demands of a disordered internal environment, a process known as "allostasis." Human cells respond to osmotic stress created by an abnormal serum sodium level with the same adaptations used by invertebrate organisms that do not regulate body fluid osmolality. To avoid intolerable changes in their volume, cells export organic osmolytes when exposed to a low serum sodium concentration and accumulate these intracellular solutes when serum sodium concentration increases. The brain's adaptation to severe hyponatremia (serum sodium < 120 mEq/L) has been studied extensively. However, adaptive responses occur with less severe hyponatremia and other tissues are affected; the consequences of these adaptations are incompletely understood. Recent epidemiologic studies have shown that mild (sodium, 130-135 mEq/L) and moderate (sodium, 121-129 mEq/L) chronic hyponatremia, long thought to be inconsequential, is associated with adverse outcomes. Adaptations of the heart, bone, brain, and (possibly) immune system to sustained mild to moderate hyponatremia may adversely affect their function and potentially the organism's survival. This review explores what is known about the consequences of mild to moderate chronic hyponatremia and the potential benefits of treating this condition.

Where Do the Salt and Water Go? A Case of Profound Hyponatremia.

Treatment of profound hyponatremia is challenging. Severe symptoms mandate correction by 4 to 6 mEq/L within hours, but with risk factors for osmotic demyelination, daily correction should be <8 mEq/L. With a therapeutic window this narrow, clinicians would like to know how serum sodium (SNa) concentration will respond to their therapy. Based on isotopic measurements, Edelman showed SNa level to be a function of exchangeable sodium and potassium divided by total-body water. Edelman defined this relationship with linear regression yielding an equation of the form y = mx + b, where y is SNa level, x is exchangeable sodium and potassium divided by total-body water, m is the slope, and b is the intercept. Edelman said that the intercept of his regression "probably is a measure of the quantity of osmotically inactive exchangeable sodium and potassium per unit of body water." Predictive formulas are derived from Edelman's original linear regression, some including and some omitting the regression's intercept. We illustrate the performance and limitations of these formulas using comprehensive data for electrolyte and fluid balance obtained during the treatment of a critically patient who presented with an SNa concentration of 101 mEq/L.

Treatment of Severe Hyponatremia.

Patients with severe (serum sodium ≤120 mEq/L), symptomatic hyponatremia can develop life-threatening or fatal complications from cerebral edema if treatment is inadequate and permanent neurologic disability from osmotic demyelination if treatment is excessive. Unfortunately, as is true of all electrolyte disturbances, there are no randomized trials to guide the treatment of this challenging disorder. Rather, therapeutic decisions rest on physiologic principles, animal models, observational studies, and single-patient reports. European guidelines and recommendations of an American Expert panel have come to similar conclusions on how much correction of hyponatremia is enough and how much is too much, but there are important differences. We review the evidence supporting these recommendations, identifying areas that rest on relatively solid ground and highlighting areas in greatest need of additional data.

Formulas for fixing serum sodium: curb your enthusiasm.

A variety of formulas have been proposed to predict changes in serum sodium concentration. All are based on an experiment done over 50 years ago by Edelman, who derived a formula relating the plasma sodium concentration to isotopically measured body sodium, potassium, and water. Some of these formulas fail because they do not include urinary losses of electrolytes and water. Even those that include these essential variables are not accurate enough for clinical use because it is impractical to adjust calculations to rapid changes in urinary composition, and because the formulas do not account for changes in serum sodium caused by internal exchanges between soluble and bound sodium stores or shifts of water into or out of cells resulting from changes in intracellular organic osmolytes. Nephrologists should curb their enthusiasm for predictive formulas and rely instead on frequent measurements of the serum sodium when correcting hyponatremia and hypernatremia.

Treatment of hyperkalemia: something old, something new.

Treatment options for hyperkalemia have not changed much since the introduction of the cation exchange resin, sodium polystyrene sulfonate (Kayexalate, Covis Pharmaceuticals, Cary, NC), over 50 years ago. Although clinicians of that era did not have ready access to hemodialysis or loop diuretics, the other tools that we use today-calcium, insulin, and bicarbonate-were well known to them. Currently recommended insulin regimens provide too little insulin to achieve blood levels with a maximal kalemic effect and too little glucose to avoid hypoglycemia. Short-acting insulins have theoretical advantages over regular insulin in patients with severe kidney disease. Although bicarbonate is no longer recommended for acute management, it may be useful in patients with metabolic acidosis or intact kidney function. Kayexalate is not effective as acute therapy, but a new randomized controlled trial suggests that it is effective when given more chronically. Gastrointestinal side effects and safety concerns about Kayexalate remain. New investigational potassium binders are likely to be approved in the coming year. Although there are some concerns about hypomagnesemia and positive calcium balance from patiromer, and sodium overload from ZS-9 (ZS Pharma, Coppell, TX), both agents have been shown to be effective and well tolerated when taken chronically. ZS-9 shows promise in the acute treatment of hyperkalemia and may make it possible to avoid or postpone the most effective therapy, emergency hemodialysis.