Can Changes in the Plasma Sodium Concentration Be Predicted Based on the Mass Balance of Sodium, Potassium, and Water in the Face of Osmotically Inactive Sodium Storage?

CONTEXT: Alterations in the plasma sodium concentration ([Na+]p) is predicted based on changes in the mass balance of Na+, K+, and H2O. However, it is well appreciated that Na+ retention results in both osmotically active and osmotically inactive Na+ storage and that only osmotically active Na+ contributes to the modulation of the [Na+]p. Subject of Review: Recent clinical studies suggested that prediction of changes in the [Na+]p based on the mass balance of Na+, K+, and H2O is inaccurate since the osmotically inactive Na+ storage pool is dynamically regulated. In contrast, animal studies demonstrated that changes in the [Na+]p can be predicted if the total body Na+, K+, and H2O were to be accurately accounted for. Second Opinion: Our analysis demonstrated that alterations in the [Na+]p are predictable at the total body level if all sources of input and output of Na+, K+, and H2O can be accurately accounted for despite the paradoxical finding that there are changes in the osmotically inactive Na+ storage pool at the tissue level. However, future prospective clinical studies are needed to corroborate the findings in the animal studies. We proposed that the fundamental question as to whether changes in the [Na+]p can be predicted in the face of osmotically inactive sodium storage is best addressed by serial measurements of total body exchangeable Na+ and K+ and total body water by isotope dilution at different time intervals.

Equivalent Efficacy and Decreased Rate of Overcorrection in Patients With Syndrome of Inappropriate Secretion of Antidiuretic Hormone Given Very Low-Dose Tolvaptan.

RATIONALE & OBJECTIVE: Euvolemic hyponatremia often occurs due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Vasopressin 2 receptor antagonists may be used to treat SIADH. Several of the major trials used 15 mg of tolvaptan as the lowest effective dose in euvolemic and hypervolemic hyponatremia. However, a recent observational study suggested an elevated risk for serum sodium level overcorrection with 15 mg of tolvaptan in patients with SIADH. STUDY DESIGN: A retrospective chart review study comparing outcomes in patients with SIADH treated with 15 versus 7.5 mg of tolvaptan. SETTINGS & PARTICIPANTS: Patients with SIADH who were treated with a very low dose of tolvaptan (7.5 mg) at a single center compared with patients using a 15-mg dose from patient-level data from the observational study described previously. PREDICTORS: Tolvaptan dose of 7.5 versus 15 mg daily. OUTCOMES: Appropriate response to tolvaptan, defined as an initial increase in serum sodium level > 3 mEq/L, and overcorrection of serum sodium level (>8 mEq/L per day, and >10 mEq/L per day in sensitivity analyses). ANALYTICAL APPROACH: Descriptive study with additional outcomes compared using t tests and F-tests (Fischer's Exact χ2 Test). RESULTS: Among 18 patients receiving 7.5 mg of tolvaptan, the mean rate of correction was 5.6 ± 3.1 mEq/L per day and 2 (11.1%) patients corrected their serum sodium levels by >8 mEq/L per day, with 1 of these increasing by >12 mEq/L per day. Of those receiving tolvaptan 7.5 mg, 14 had efficacy, with increases ≥ 3 mEq/L; similar results were seen with the 15-mg dose (21 of 28). There was a statistically significant higher chance of overcorrection with the use of 15 versus 7.5 mg of tolvaptan (11 of 28 vs 2 of 18; P = 0.05; and 10 of 28 vs 1 of 18; P = 0.03, for >8 mEq/L per day and >10 mEq/L per day, respectively). LIMITATIONS: Small sample size, retrospective, and nonrandomized. CONCLUSIONS: Tolvaptan, 7.5 mg, daily corrects hyponatremia with similar efficacy and less risk for overcorrection in patients with SIADH versus 15 mg of tolvaptan.

Is the Osmolal Concentration of Ethanol Greater Than Its Molar Concentration?

Background: Recent data suggested that the osmolal gap attributed to ethanol as determined by the difference between measured serum osmolality and calculated serum osmolarity is greater than its molar concentration. The increased osmotic activity of ethanol is thought to be due to its binding to water molecules. This study is conducted to determine the true osmotic contribution of ethanol to serum osmolality. Methods: Baseline serum osmolality and ethanol concentration were measured on each serum sample. Varying amounts of ethanol were added to aliquots of serum in which the baseline serum ethanol concentration was undetectable. Repeat serum osmolality and serum ethanol concentration were measured after addition of ethanol. Results: The range of serum ethanol concentration was 27.3-429.8 mg/dL. The serum osmolal gap attributed solely to ethanol is calculated based on the difference between measured serum osmolality before and measured serum osmolality after addition of ethanol. Our results demonstrated that the contribution of ethanol to serum osmolality can be calculated by dividing the serum ethanol level in mg/dl by 4.6. In addition, the relationship between serum ethanol concentration and osmolal gap due to ethanol was assessed by linear regression analysis. Linear regression analysis relating the osmolal gap due to ethanol and ethanol concentration yielded the following equation: Osmolal Gap (mOsm/kg H2O) = 0.23 (Ethanol [mg/dL]) - 1.43. Conclusion: The osmolal concentration of ethanol can be calculated based on its molar concentration. We found no evidence for ethanol binding to water molecules over the range of ethanol concentration in this study.

Treatment of Cirrhosis-Associated Hyponatremia with Midodrine and Octreotide.

BACKGROUND: Hyponatremia in the setting of cirrhosis is a common electrolyte disorder with few therapeutic options. The free water retention is due to non-osmotic vasopressin secretion resulting from the cirrhosis-associated splanchnic vasodilatation. Therefore, vasoconstrictive therapy may correct this electrolyte abnormality. The aim of this study was to assess the efficacy of midodrine and octreotide as a therapeutic approach to increasing urinary electrolyte-free water clearance (EFWC) in the correction of cirrhosis-associated hyponatremia. METHODS: This observational study consisted of 10 patients with cirrhosis-associated hyponatremia. Hypovolemia was ruled out as the cause of the hyponatremia with a 48-h albumin challenge (25 g IV q6 h). Patients whose hyponatremia failed to improve with albumin challenge were started on midodrine and octreotide at 10 mg po tid and 100 µg sq tid, respectively, with rapid up-titration as tolerated to respective maximal doses of 15 mg tid and 200 µg tid within the first 24 h. We assessed urinary EFWC and serum sodium concentration before and 72 h after treatment. RESULTS: Pretreatment serum sodium levels ranged from 119 to 133 mmol/L. The mean pretreatment serum sodium concentration ± SEM was 124 mmol/L ± 1.6 vs 130 mmol/L ± 1.5 posttreatment (p = 0.00001). The mean pretreatment urinary EFWC ± SEM was 0.33 L ± 0.07 vs 0.82 L ± 0.11 posttreatment (p = 0.0003). CONCLUSION: Our data show a statistically significant increase in serum sodium concentration and urinary EFWC with the use of midodrine and octreotide in the treatment of cirrhosis-associated hyponatremia.

Osmotically inactive sodium and potassium storage: lessons learned from the Edelman and Boling data.

Because changes in the plasma water sodium concentration ([Na(+)]pw) are clinically due to changes in the mass balance of Na(+), K(+), and H2O, the analysis and treatment of the dysnatremias are dependent on the validity of the Edelman equation in defining the quantitative interrelationship between the [Na(+)]pw and the total exchangeable sodium (Nae), total exchangeable potassium (Ke), and total body water (TBW) (Edelman IS, Leibman J, O'Meara MP, Birkenfeld LW. J Clin Invest 37: 1236-1256, 1958): [Na(+)]pw = 1.11(Nae + Ke)/TBW - 25.6. The interrelationship between [Na(+)]pw and Nae, Ke, and TBW in the Edelman equation is empirically determined by accounting for measurement errors in all of these variables. In contrast, linear regression analysis of the same data set using [Na(+)]pw as the dependent variable yields the following equation: [Na(+)]pw = 0.93(Nae + Ke)/TBW + 1.37. Moreover, based on the study by Boling et al. (Boling EA, Lipkind JB. 18: 943-949, 1963), the [Na(+)]pw is related to the Nae, Ke, and TBW by the following linear regression equation: [Na(+)]pw = 0.487(Nae + Ke)/TBW + 71.54. The disparities between the slope and y-intercept of these three equations are unknown. In this mathematical analysis, we demonstrate that the disparities between the slope and y-intercept in these three equations can be explained by how the osmotically inactive Na(+) and K(+) storage pool is quantitatively accounted for. Our analysis also indicates that the osmotically inactive Na(+) and K(+) storage pool is dynamically regulated and that changes in the [Na(+)]pw can be predicted based on changes in the Nae, Ke, and TBW despite dynamic changes in the osmotically inactive Na(+) and K(+) storage pool.

Defining the role of albumin infusion in cirrhosis-associated hyponatremia.

The presence of negatively charged, impermeant proteins in the plasma space alters the distribution of diffusible ions in the plasma and interstitial fluid (ISF) compartments to preserve electroneutrality and is known as Gibbs-Donnan equilibrium. In patients with hypoalbuminemia due to underlying cirrhosis, the decrease in the plasma water albumin concentration ([Alb-]pw) would be expected to result in a decrease in the plasma water sodium concentration ([Na+]pw) due to an alteration in the distribution of Na+ between the plasma and ISF. In addition, cirrhosis-associated hyponatremia may be due to the renal diluting defect resulting from the intravascular volume depletion due to gastrointestinal losses and overdiuresis and/or decreased effective circulatory volume secondary to splanchnic vasodilatation. Therefore, albumin infusion may result in correction of the hyponatremia in cirrhotic patients either by modulating the Gibbs-Donnan effect due to hypoalbuminemia or by restoring intravascular volume in patients with intravascular volume depletion due to gastrointestinal losses and overdiuresis. However, the differential role of albumin infusion in modulating the [Na+]pw in these patients has not previously been analyzed quantitatively. In the present study, we developed an in vitro assay system to examine for the first time the quantitative effect of changes in albumin concentration on the distribution of Na+ between two compartments separated by a membrane that allows the free diffusion of Na+. Our findings demonstrated that changes in [Alb-]pw are linearly related to changes in [Na+]pw as predicted by Gibbs-Donnan equilibrium. However, based on our findings, we predict that the improvement in cirrhosis-associated hyponatremia due to intravascular volume depletion results predominantly from the restoration of intravascular volume rather than alterations in Gibbs-Donnan equilibrium.

Defining the buffering process by a triprotic acid without relying on Stewart-electroneutrality considerations.

Upon the addition of protons to an aqueous solution, a component of the H+ load will be bound i.e. buffered. In an aqueous solution containing a triprotic acid, H+ can be bound to three different states of the acid as well as to OH- ions that are derived from the auto-ionization of H2O. In quantifying the buffering process of a triprotic acid, one must define the partitioning of H+ among the three states of the acid and also the OH- ions in solution in order to predict the equilibrium pH value. However, previous quantitative approaches that model triprotic acid titration behaviour and used to predict the equilibrium pH rely on the mathematical convenience of electroneutrality/charge balance considerations. This fact has caused confusion in the literature, and has led to the assumption that charge balance/electroneutrality is a causal factor in modulating proton buffering (Stewart formulation). However, as we have previously shown, although charge balance can be used mathematically as a convenient tool in deriving various formulae, electroneutrality per se is not a fundamental physicochemical parameter that is mechanistically involved in the underlying buffering and proton transfer reactions. The lack of distinction between a mathematical tool, and a fundamental physicochemical parameter is in part a reason for the current debate regarding the Stewart formulation of acid-base analysis. We therefore posed the following question: Is it possible to generate an equation that defines and predicts the buffering of a triprotic acid that is based only on H+ partitioning without incorporating electroneutrality in the derivation? Towards this goal, we derived our new equation utilizing: 1) partitioning of H+ buffering; 2) conservation of mass; and 3) acid-base equilibria. In validating this model, we compared the predicted equilibrium pH with the measured pH of an aqueous solution consisting of Na2HPO4 to which HCl was added. The measured pH values were in excellent agreement with the predictions of our equation. Our results provide further important evidence that one can mathematically model the chemistry of acid-base phenomenology without relying on electroneutrality (Stewart formulation) considerations.

Quantitative approaches to the analysis and treatment of the dysnatremias.

Recent new insights into the determinants of the plasma water sodium concentration ([Na(+)](pw)) have played an important role in advancing our understanding of the pathogenesis and treatment of the dysnatremias. Central to these recent advances is the recognition of the full significance of the Edelman equation discovered 50 years ago. Although Edelman et al showed empirically that the [Na(+)](pw) is related to the total exchangeable sodium (Na(e)), total exchangeable potassium (K(e)), and total body water (TBW) by the following equation: [Na(+)](pw) = 1.11(Na(e) + K(e))/TBW - 25.6 (Eq. 1), the significance of the nonzero values of the slope and y-intercept in the Edelman equation has been unrecognized and ignored. It recently has been shown that the slope and y-intercept in this equation are determined quantitatively by several additional physiologic parameters that play an important role in modulating the [Na(+)](pw) and in the generation of the dysnatremias. By defining all the physiologic parameters that determine the magnitude of the [Na(+)](pw), this analysis has also proven to be an indispensable tool for deriving new formulas to aid the clinician in both interpreting the pathogenesis and treating the dysnatremias. In this article, the role of quantitative analysis in the diagnostic and therapeutic approach to the dysnatremias is discussed.

Calculation of the equilibrium pH in a multiple-buffered aqueous solution based on partitioning of proton buffering: a new predictive formula.

Upon the addition of protons to an aqueous solution containing multiple buffers, the final H+ concentration ([H+]) at equilibrium is determined by the partitioning of added H+ among the various buffer components. In the analysis of acid-base chemistry, the Henderson-Hasselbalch equation and the Stewart strong ion formulation can only describe (rather than predict) the equilibrium pH following a proton load since these formulas calculate the equilibrium pH only when the reactant concentrations at equilibrium(1) 1The term "equilibrium" refers to the steady state proton and reactant concentrations when the buffering of excess protons by the various buffers is complete. are already known. In this regard, it is simpler to directly measure the equilibrium pH rather than measure the equilibrium reactant concentrations to calculate the equilibrium pH. As these formulas cannot predict the final equilibrium [H+] following a proton load to a multiple-buffered aqueous solution, we developed a new quantitative approach for predicting the equilibrium [H+] that is based on the preequilibrium(2)2 The term "preequilibrium" refers to the initial proton and reactant concentrations immediately upon addition of protons and before the buffering of excess protons by the various buffers. concentrations of all buffers in an aqueous solution. The mathematical model used to derive our equation is based on proton transfer buffer equilibria without requiring the incorporation of electroneutrality considerations. The model consists of a quartic polynomial equation that is derived based solely on the partitioning of H+ among the various buffer components. We tested the accuracy of the model using aqueous solutions with various buffers and measured the equilibrium pH values following the addition of HCl. Our results confirmed the accuracy of our new equation (r2 = 1; measured pH vs. predicted pH), indicating that it quantitatively accounts for the underlying acid-base phenomenology.

Correction of hypervolaemic hypernatraemia by inducing negative Na+ and K+ balance in excess of negative water balance: a new quantitative approach.

BACKGROUND: Hypervolemic hypernatremia is caused by an increase in total exchangeable Na(+) and K(+) in excess of an increment in total body H(2)O (TBW). Unlike patients with hypovolemic or euvolemic hypernatremia, treatment needs to be targeted at correcting not only the elevated plasma Na(+) concentration, but also there is an additional requirement to achieve negative H(2)O balance to correct the increment in TBW. METHODS: Correction of hypervolemic hypernatremia can be attained by ensuring that the negative Na(+) and K(+) balance exceeds the negative H(2)O balance. These seemingly conflicting therapeutic goals are typically approached by administering intravenous 5% Dextrose (IV D5W) and furosemide. RESULTS: Currently, there is no quantitative approach to predicting the volume of IV D5W (V(IVF)) that needs to be administered that satisfies these requirements. Therefore, based on the principle of mass balance and the empirical relationship between exchangeable Na(+), K(+), TBW, and the plasma Na(+) concentration, we have derived a new equation which calculates the volume of IV D5W (V(IVF)) needed to lower the plasma Na(+) concentration ([Na(+)](p1)) to a targeted level ([Na(+)](p2)) by achieving the desired amount of negative H(2)O balance (V(MB)): V(IVF) = {([Na(+)](p1) + 23.8) (TBW(1)) - ([Na(+)](p2) + 23.8)(TBW(1) + V(MB)) + 1.03 ([E](input) x V(input) - [E](output) x V(output) - [E](urine) (V(input) - V(output) - V(MB)))}/1.03 x [E](urine) where [E] = [Na(+) + K(+)] and input and output refer to non-infusate and non-renal input and output respectively. CONCLUSION: This new formula is the first quantitative approach for correcting hypervolemic hypernatremia by achieving negative Na(+) and K(+) balance in excess of negative H(2)O balance.

Acid-base analysis: a critique of the Stewart and bicarbonate-centered approaches.

When approaching the analysis of disorders of acid-base balance, physical chemists, physiologists, and clinicians, tend to focus on different aspects of the relevant phenomenology. The physical chemist focuses on a quantitative understanding of proton hydration and aqueous proton transfer reactions that alter the acidity of a given solution. The physiologist focuses on molecular, cellular, and whole organ transport processes that modulate the acidity of a given body fluid compartment. The clinician emphasizes the diagnosis, clinical causes, and most appropriate treatment of acid-base disturbances. Historically, two different conceptual frameworks have evolved among clinicians and physiologists for interpreting acid-base phenomena. The traditional or bicarbonate-centered framework relies quantitatively on the Henderson-Hasselbalch equation, whereas the Stewart or strong ion approach utilizes either the original Stewart equation or its simplified version derived by Constable. In this review, the concepts underlying the bicarbonate-centered and Stewart formulations are analyzed in detail, emphasizing the differences in how each approach characterizes acid-base phenomenology at the molecular level, tissue level, and in the clinical realm. A quantitative comparison of the equations that are currently used in the literature to calculate H(+) concentration ([H(+)]) is included to clear up some of the misconceptions that currently exist in this area. Our analysis demonstrates that while the principle of electroneutrality plays a central role in the strong ion formulation, electroneutrality mechanistically does not dictate a specific [H(+)], and the strong ion and bicarbonate-centered approaches are quantitatively identical even in the presence of nonbicarbonate buffers. Finally, our analysis indicates that the bicarbonate-centered approach utilizing the Henderson-Hasselbalch equation is a mechanistic formulation that reflects the underlying acid-base phenomenology.

A new method for determining plasma water content: application in pseudohyponatremia.

Pseudohyponatremia is a clinical condition characterized by an increased fraction of protein or lipid in plasma, thereby resulting in an artificially low plasma sodium concentration ([Na(+)](p)). Since the automated method of measuring [Na(+)](p) in most laboratories involves the use of an indirect ion-selective electrode (I-ISE), this method does not correct for elevated protein or lipid concentrations. In I-ISE, the plasma sample is diluted before the actual measurement is obtained, and the [Na(+)](p) is determined based on the assumption that plasma is normally composed of 93% plasma water. Therefore, the [Na(+)](p) as determined by I-ISE will be artificially low in clinical conditions when the plasma water content (PWC) is <93%. In contrast, the plasma is not diluted when the [Na(+)](p) is measured using direct ISE (D-ISE). This method directly measures Na(+) activity in plasma water and is therefore unaffected by the proportion of plasma occupied by water. In this study, we report a novel quantitative method for determining the PWC utilizing I-ISE and D-ISE. To validate this new method experimentally, we altered the PWC in vitro by dissolving varying amount of salt-free albumin in human plasma. We then measured PWC gravimetrically in each sample and compared the gravimetrically determined PWC with the ISE-determined PWC. Our findings indicate that the PWC can be accurately determined based on differences in the [Na(+)](p) as measured by I-ISE and D-ISE and that this new quantitative method can be a useful adjunct in the analysis of the dysnatremias.

Acute lymphoblastic leukemia presenting as acute renal failure.

BACKGROUND: A 42-year-old previously healthy man presented with acute-onset headache and facial paralysis. He was treated for Bell's palsy with corticosteroids and valaciclovir. One week later, he developed acute renal failure requiring hospitalization. INVESTIGATION: Physical examination, laboratory tests, urinalysis, renal ultrasound, renal biopsy, bone marrow biopsy, lumbar puncture, CT of the chest, abdomen and pelvis, MRI of the brain, and whole-body PET scan. DIAGNOSIS: Acute lymphoblastic leukemia, bilateral renal enlargement secondary to leukemic infiltration, acute renal failure, tumor lysis syndrome, and leukemic involvement of the facial nerve. MANAGEMENT: The patient was treated with a modified induction chemotherapy regimen. He was given allopurinol for hyperuricemia and hydrated with alkalized intravenous fluids to prevent uric acid precipitation in the renal tubules. The profound tumor lysis that occurred after the cytotoxic chemotherapy required hemodialysis.

Is the osmotically inactive sodium storage pool fixed or variable?

Recently, there is renewed interest in the role of osmotically inactive Na(+) storage during Na(+) retention. Although it is well accepted that a portion of the total exchangeable Na(+) reservoir is osmotically inactive, there is current controversy as to whether the osmotically inactive Na(+) storage pool is fixed or variable during Na(+) retention. In this article, we analyze the current scientific evidence to assess whether the osmotically inactive Na(+) storage pool can be dynamically regulated. Our analysis supports the assertion that the osmotically inactive Na(+) storage pool is fixed rather than variable.

Fatal hyponatremia in a young woman after ecstasy ingestion.

BACKGROUND: A 20-year old, otherwise healthy, female college student presented in an unresponsive state with respiratory distress after ingesting ecstasy (3,4-methylenedioxymethamphetamine). She had initial plasma sodium concentration of 117 mmol/l. INVESTIGATIONS: Physical examination, blood chemistry panel, urinary osmolality and electrolytes, arterial blood gas, chest X-ray, and CT scan of the brain. DIAGNOSIS: Hyponatremia associated with noncardiogenic pulmonary edema and cerebral edema. MANAGEMENT: Administration of a total of 6.8 l of isotonic saline and 0.245 l of 3% hypertonic saline with sporadic administration of intravenous furosemide. The patient died approximately 12 h after admission.

True hyponatremia secondary to intravenous immunoglobulin.

Hyponatremia is characterized as either "true hyponatremia," which represents a decrease in the Na(+) concentration in the water phase of plasma, or "pseudohyponatremia," which is due to an increased percentage of protein or lipid in plasma, with a normal plasma water Na(+) concentration ([Na(+)]). Pseudohyponatremia is a known complication of intravenous immunoglobulin (IVIG). Because IVIG has been reported to result in post-infusional hyperproteinemia, IVIG-induced hyponatremia has been attributed to pseudohyponatremia. In this case report, we demonstrate that IVIG therapy can result in true hyponatremia, resulting from sucrose-induced translocation of water from the intracellular compartment (ICF) to the extracellular compartment (ECF), as well as the infusion of a large volume of dilute fluid, in patients with an underlying defect in urinary free water excretion.

Whole-body electrolyte-free water clearance: derivation and clinical utility in analyzing the pathogenesis of the dysnatremias.

The total exchangeable sodium (Na(e)), total exchangeable potassium (K(e)), and total body water (TBW) are the major determinants of the plasma water sodium concentration ([Na(+)](pw)). The relationship between [Na(+)](pw) and Na(e), K(e), and TBW was empirically determined by Edelman et al., where: [Na(+)](pw) = 1.11(Na(e) + K(e))/TBW - 25.6 (Eq. 1). According to Eq. 1, changes in the mass balance of Na(+), K(+), and H(2)O will therefore result in changes in the [Na(+)](pw). Historically, in evaluating the pathogenesis of the dysnatremias, free water clearance (FWC) and electrolyte-free water clearance (EFWC) have been used to evaluate the pathophysiology of the dysnatremias. However, such analyses are only valid when there is no concomitant input and non-renal output of Na(+), K(+), and H(2)O. Since the classic FWC and EFWC formulas fail to account for the input and non-renal output of Na(+), K(+), and H(2)O, these formulas cannot be used to evaluate the pathogenesis of the dysnatremias or to predict the directional change in the [Na(+)](pw). In this article, we have addressed this limitation by deriving a new formula, termed whole-body electrolyte-free water clearance (WB-EFWC), which calculates whole-body electrolyte-free water clearance for a given mass balance of Na(+), K(+), and H(2)O, rather than simply the urinary component (FWC, EFWC formulas). Unlike previous formulas, which consider only the renal component of electrolyte-free water clearance, WB-EFWC accounts for all sources of input and output of Na(+), K(+), and H(2)O, and will therefore be helpful in conceptually understanding the basis for changes in the [Na(+)](pw) in patients with the dysnatremias.