Minhtri K. Nguyen

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.

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.

A new quantitative approach to the treatment of the dysnatremias.

Rapid correction of the dysnatremias can result in significant patient morbidity and mortality. To avoid overly rapid correction of the dysnatremias, the sodium deficit equation, water deficit equation, and Adrogue–Madias equation are frequently utilized to predict the change in plasma sodium concentration (Δ[Na+]p) following a therapeutic maneuver. However, there are significant limitations inherent in these equations. Specifically, the sodium deficit equation assumes that total body water (TBW) remains unchanged. Similarly, when using the Adrogue–Madias equation, the volume of infusate required to induce a given Δ[Na+]p is determined by dividing the target Δ[Na+]p by the result of this formula. This calculation also assumes that TBW remains constant. In addition, neither of these equations are applicable in the management of symptomatic syndrome of inappropriate antidiuretic hormone secretion (SIADH) because they fail to consider the subsequent increase in sodium excretion following the administration of infusate. Furthermore, in the treatment of hypernatremia, the water deficit equation is only applicable if the hypernatremia is caused by pure water loss. In hypernatremia caused by hypotonic fluid losses, the water deficit equation does not provide any information on the differential effect of infusates of variable [Na+] and [K+] on the [Na+]p. Finally, all these equations fail to consider any ongoing Na+, K+, or H2O losses. Taking all these limitations into consideration, we have derived two new equations which determine the volume of a given infusate required to induce a target Δ[Na+]p. These equations consider the mass balance of Na+, K+, and H2O, as well as therapy-induced changes in TBW. The first equation is applicable to both hypernatremia and hyponatremia. The second equation is applicable to the management of severe symptomatic SIADH requiring intravenous therapy.

A simple quantitative approach to analyzing the generation of the dysnatremias

AbstractBackground. Although the dysnatremias are the most common electrolyte disorders in hospitalized patients, the complexity of the parameters normally used to explain their generation mechanistically is often bewildering to medical students and experts alike. A number of methods have been utilized clinically to analyze retrospectively and predict prospectively the pathogenesis of these disorders. These approaches include the measurements of plasma and urine osmolality, free water clearance, electrolyte free water clearance, and tonicity balance. Methods. All previous analyses are problematic in that they fail to incorporate mathematically in a single equation the known factors that account quantitatively for changes in the plasma water sodium concentration. In this paper, we have derived a simple formula for use at the bedside based on all known factors that can generate the dysnatremias. The formula incorporates (1) the known empirical relationship between the plasma water Na+ concentration, total body water (TBW), and exchangeable Na+ (Na+e) and K+ (K+e); (2) changes in mass balance of H2O (VMB) and Na+ + K+ (EMB); and (3) the effect of hyperglycemia. Results. This new equation, unlike all previous qualitative and quantitative approaches, can account mathematically for the simultaneous effects of TBW, Nae, Ke, EMB, VMB, and the plasma glucose on the plasma water sodium concentration. Clinical examples are provided that demonstrate the utility of this new equation in analyzing the pathogenesis of the dysnatremias. Conclusion. The conceptual simplification resulting from the use of this formula should significantly improve the current approaches used in analyzing the generation of the dysnatremias.

Role of potassium in hypokalemia-induced hyponatremia: lessons learned from the Edelman equation.

It is well known that changes in the mass balance of K+ can lead to an alteration in the plasma water sodium concentration ([Na+ ]pw). We have recently shown that based on the Edelman equation, the [Na+ ]pw is determined by the total exchangeable Na+ (Nae), total exchangeable K+ (Ke), total body water (TBW), osmotically inactive Nae and Ke, plasma water [K+], intracellular and extracellular osmotically active non-Na+ and non-K+ osmoles, and plasma osmotically active non-Na+ and non-K+ osmoles. In light of these findings, a re-analysis of the role of K+ in modulating the [Na+]pw is required in understanding the pathophysiology of hypokalemia-induced hyponatremia. In this article, we characterize the complex role of K+ in the pathogenesis of hypokalemia-induced hyponatremia using a three-compartment model and the known parameters in the Edelman equation. Our analysis indicates that K+ modulates the [Na+]pw by changing Ke in addition to the parameters in the y-intercept of the Edelman equation. Moreover, the magnitude of potassium-induced changes in the [Na+]pw is determined by the pathophysiologic mechanisms by which changes in Ke occur.

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.

Molecular pathogenesis of nephrogenic diabetes insipidus

There have been significant advances recently in the understanding of the molecular causes of nephrogenic diabetes insipidus. The resistance of the collecting duct to the action of vasopressin in this disorder results from abnormalities in several of the intricate steps that mediate the increase in principal cell hydraulic conductivity in response to the hormone. In this article, we review the current understanding of the known genetic causes of nephrogenic diabetes insipidus that affect the binding of vasopressin to the V2 receptor and subsequent intracellular signaling events, as well as the translocation of aquaporin-2 water channels to the apical membrane. In addition, genetic diseases, which decrease collecting-duct water absorption by diminishing the interstitial medullary osmolarity, are discussed.

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 Bells 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.

Analysis of current formulas used for treatment of the dysnatremias.

Hyponatremia is a common electrolyte disorder encountered in hospitalized patients. The complexity of the various sources of fluid and electrolyte input and output in these patients, especially those admitted to the intensive care unit (ICU), makes it difficult to predict accurately the effect of a given course of therapy on changes in the plasma sodium concentration (D[Na ]p). Indeed, there is evidence that inappropriate treatment of this disorder may contribute significantly to the patients’ morbidity and mortality. Rapid correction of chronic hyponatremia can cause osmotic demyelination, resulting in quadriplegia, pseudobulbar palsy, seizures, coma, and even death. Consequently, it has been recommended that the targeted rate of correction of the [Na ]p should not exceed 0.5mEq/L/h or 12mEq/L/day. Several formulas, including the sodium deficit equation, Androgue-Madias equation, Barsoum-Levine equation, and Nguyen-Kurtz equation, are utilized to predict the magnitude of the increase in [Na ]p following the administration of intravenous fluid. The strengths and weaknesses of these formulas are not typically considered by clinicians prior to choosing the appropriate fluid to administer to a given patient. Given the morbidity that can potentially result from inappropriately treating patients with dysnatremias, in this article we review in detail the assumptions on which these formulas are based. A teaching case is utilized to demonstrate the clinical utility of these formulas and to highlight the potential pitfalls which clinicians need to be aware of when managing patients with dysnatremias.

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.