Edelman Gamblegrams: a tool to teach and learn disorders of water/plasma tonicity homeostasis.

This article introduces an innovative teaching and learning tool called "Edelman Gamblegrams" that aims to help medical learners better understand disorders related to water/plasma tonicity homeostasis, i.e., hyponatremia and hypernatremia. Gamblegrams, named after physician James L. Gamble, are bar diagrams displaying the relative abundance of extracellular anions and cations and are commonly used in the analysis of acid-base disorders. The Edelman equation represents the physiological variables that determine plasma sodium concentration, namely, total body sodium mass, total body potassium mass, and total body water volume. Edelman Gamblegrams inspired by traditional Gamblegrams but using the components of the Edelman equation, visually demonstrate how sodium, potassium, and water contribute to plasma sodium concentration under normal and pathological conditions. Scenarios that lead to hypotonic hyponatremia and hypernatremia in Edelman Gamblegrams are also discussed. Furthermore, examples of how these visual aids can enhance understanding of the pathogenesis of dysnatremias are also presented. Overall, the use of Edelman Gamblegrams has the potential to improve comprehension and retention of concepts related to water/plasma tonicity homeostasis.NEW & NOTEWORTHY This article introduces a new teaching tool called "Edelman Gamblegrams," modeled after the conventional Gamblegrams used in acid-base disorder analysis and using the independent physiological variables that determine the plasma sodium concentration (Edelman equation), that aims to help medical learners understand disorders related to water/plasma tonicity homeostasis.

Diagnostic and Therapeutic Strategies to Severe Hyponatremia in the Intensive Care Unit.

Hyponatremia is the most common electrolyte abnormality encountered in critically ill patients and is linked to heightened morbidity, mortality, and healthcare resource utilization. However, its causal role in these poor outcomes and the impact of treatment remain unclear. Plasma sodium is the main determinant of plasma tonicity; consequently, hyponatremia commonly indicates hypotonicity but can also occur in conjunction with isotonicity and hypertonicity. Plasma sodium is a function of total body exchangeable sodium and potassium and total body water. Hypotonic hyponatremia arises when total body water is proportionally greater than the sum of total body exchangeable cations, that is, electrolyte-free water excess; the latter is the result of increased intake or decreased (kidney) excretion. Hypotonic hyponatremia leads to water movement into brain cells resulting in cerebral edema. Brain cells adapt by eliminating solutes, a process that is largely completed by 48 h. Clinical manifestations of hyponatremia depend on its biochemical severity and duration. Symptoms of hyponatremia are more pronounced with acute hyponatremia where brain adaptation is incomplete while they are less prominent in chronic hyponatremia. The authors recommend a physiological approach to determine if hyponatremia is hypotonic, if it is mediated by arginine vasopressin, and if arginine vasopressin secretion is physiologically appropriate. The treatment of hyponatremia depends on the presence and severity of symptoms. Brain herniation is a concern when severe symptoms are present, and current guidelines recommend immediate treatment with hypertonic saline. In the absence of significant symptoms, the concern is neurologic sequelae resulting from rapid correction of hyponatremia which is usually the result of a large water diuresis. Some studies have found desmopressin useful to effectively curtail the water diuresis responsible for rapid correction.

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.

Hyponatremia Demystified: Integrating Physiology to Shape Clinical Practice.

Hyponatremia is one of the most common problems encountered in clinical practice and one of the least-understood because accurate diagnosis and management require some familiarity with water homeostasis physiology, making the topic seemingly complex. The prevalence of hyponatremia depends on the nature of the population studied and the criteria used to define it. Hyponatremia is associated with poor outcomes including increased mortality and morbidity. The pathogenesis of hypotonic hyponatremia involves the accumulation of electrolyte-free water caused by either increased intake and/or decrease in kidney excretion. Plasma osmolality, urine osmolality, and urine sodium can help to differentiate among the different etiologies. Brain adaptation to plasma hypotonicity consisting of solute extrusion to mitigate further water influx into brain cells best explains the clinical manifestations of hyponatremia. Acute hyponatremia has an onset within 48 hours, commonly resulting in severe symptoms, while chronic hyponatremia develops over 48 hours and usually is pauci-symptomatic. However, the latter increases the risk of osmotic demyelination syndrome if hyponatremia is corrected rapidly; therefore, extreme caution must be exercised when correcting plasma sodium. Management strategies depend on the presence of symptoms and the cause of hyponatremia and are discussed in this review.

Spurious Electrolyte and Acid-Base Disorders in the Patient With Cancer: A Review.

Electrolyte and acid-base disorders are frequently encountered in patients with malignancy, either due to cancer itself or as a complication of its therapy. However, spurious electrolyte disorders can complicate the interpretation and management of these patients. Several electrolytes can be artifactually increased or decreased such that the serum electrolyte values do not correspond to their actual systemic levels, potentially resulting in extensive diagnostic investigations and therapeutic interventions. Examples of spurious derangements include pseudohyponatremia, pseudohypokalemia, pseudohyperkalemia, pseudohypophosphatemia, pseudohyperphosphatemia, and artifactual acid-base abnormalities. Correctly interpreting these artifactual laboratory abnormalities is imperative for avoiding unnecessary and potentially harmful interventions in cancer patients. The factors influencing these spurious results also must be recognized, along with the steps to minimize them. We present a narrative review of commonly reported pseudo electrolyte disorders and describe strategies to exclude erroneous interpretations of these laboratory values and avoid pitfalls. Awareness and recognition of spurious electrolyte and acid-base disorders can prevent unnecessary and harmful treatments.

Hyponatremia in Cirrhosis.

Hyponatremia is the most common electrolyte disorder encountered in clinical practice, and it is a common complication of cirrhosis reflecting an increase in nonosmotic secretion of arginine vasopressin as a result of of the circulatory dysfunction that is characteristic of advanced liver disease. Hyponatremia in cirrhosis has been associated with poor clinical outcomes including increased risk of morbidity and mortality, poor quality of life, and heightened health care utilization. Despite this, the treatment of hyponatremia in cirrhosis remains challenging as conventional therapies such as fluid restriction are frequently ineffective. In this review, we discuss the epidemiology, clinical outcomes, pathogenesis, etiology, evaluation, and management of hyponatremia in cirrhosis.

Electrolyte and Acid-Base Disorders Associated with Cancer Immunotherapy.

Novel immunotherapy drugs have changed the landscape of cancer medicine. Immune checkpoint inhibitors and chimeric antigen receptor T cells are being used and investigated in almost all types of cancers. Immune-related adverse events have been associated with immunotherapies. AKI has been the most commonly associated kidney adverse event. In this review, we showcase the several associated electrolyte disorders seen with immunotherapy. Immune checkpoint inhibitors can lead to hyponatremia by several mechanisms, with the syndrome of inappropriate antidiuresis being the most common. Endocrine causes of hyponatremia are rare. Hypokalemia is not uncommon and is associated with both proximal and distal renal tubular acidosis. Hypercalcemia associated with immune checkpoint inhibitors has led to some interesting observations, including immune checkpoint inhibitor-induced parathyroid hormone-related peptide production, sarcoid-like granulomas, and hyperprogression of the disease. Hypocalcemia and hyperphosphatemia may be seen with immune checkpoint inhibitor-induced tumor lysis syndrome. Chimeric antigen receptor T cell therapy-associated electrolyte disorders are also common. This is associated chiefly with hyponatremia, although other electrolyte abnormalities can occur. Early recognition and prompt diagnosis may help providers manage the mechanistically varied and novel electrolyte disorders associated with immunotherapy.

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.

Hypophosphatemia in cancer patients.

Dysregulation of phosphorus homeostasis resulting in hypophosphatemia is common in cancer patients and can result in serious complications and impact outcomes. Several factors, including critical illness, nutritional status, cancer type and therapy, influence the development of hypophosphatemia. Hypophosphatemia can develop as a result of phosphaturic mesenchymal tumors or as a paraneoplastic phenomenon. The clinical presentation for hypophosphatemia varies depending on the duration and severity of the hypophosphatemia and affects several organ systems. Among other serious effects, hypophosphatemia can impair tissue oxygenation and can cause hemolysis, leukocyte and platelet dysfunction, encephalopathy, seizures, arrhythmias, cardiomyopathy, rhabdomyolysis and coma. Multiple studies have demonstrated that hypophosphatemia is an adverse prognostic marker in inpatients with increased in-hospital stay, mortality and postoperative complications. The phosphate level is homeostatically regulated and maintained in a narrow range by three main hormones: parathyroid hormone, fibroblast growth factor 23 and 1,25-dihydroxyvitaminD3. Together, these hormones regulate how the intestine, kidneys and bones traffic phosphorus. Several hematological malignancies and cancer therapies are associated with proximal tubular dysfunction (Fanconi syndrome), resulting in phosphaturia. Caution should be taken with parenteral administration of phosphate salts, because secondary complications can develop, principally due to hypocalcemia. The general approach to hypophosphatemia should target the underlying cause. Early recognition and prevention are essential and the approach to hypophosphatemia in the cancer patient, because of the nuances and complexity, should be multidisciplinary.

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.

Hypomagnesemia in the Cancer Patient.

Hypomagnesemia is a common medical problem that contributes to the morbidity and mortality of patients with cancer. This review summarizes magnesium physiology and highlights the mechanisms underlying magnesium disturbances due to cancer and cancer treatment. The causes of hypomagnesemia can be categorized according to the pathophysiologic mechanism: decreased intake, transcellular shift, gastrointestinal losses, and kidney losses. Patients with cancer are at risk for opportunistic infections, frequently experience cardiovascular complications, and often receive classes of medications that cause or exacerbate hypomagnesemia. Also, cancer-specific therapies are responsible for hypomagnesemia, including platinum-based chemotherapy, anti-EGF receptor mAbs, human EGF receptor-2 target inhibitors (HER2), and calcineurin inhibitors. Urinary indices, such as the fractional excretion of magnesium, can provide useful information about the etiology. The management of hypomagnesemia depends on the magnitude of hypomagnesemia and the underlying cause. We recommended checking serum magnesium at the beginning of treatment and as part of routine monitoring throughout cancer treatment. Opportunities exist for potential research and practice improvement, including further characterization of hypomagnesemia regarding the clinical effect on cancer outcomes, preventing hypomagnesemia in patients receiving high-risk anticancer agents, and developing effective therapeutic strategies.

Hyponatremia in the cancer patient.

Hyponatremia is a common electrolyte disorder observed in a wide variety of malignancies and is associated with substantial morbidity and mortality. Newer cancer therapies have improved patient outcomes while contributing to new cases of hyponatremia. Patients should be monitored closely for the development of vasopressin- and non-vasopressin-mediated hyponatremia. Acute and symptomatic forms of hyponatremia require urgent intervention, and recent findings support the correction of chronic "asymptomatic" hyponatremia. Optimizing hyponatremia may reduce medical costs, and improve cancer survival likelihood and quality of life. In this article, we review the epidemiology, pathophysiology, etiology, diagnosis, and treatment of hyponatremia in the cancer patient.

Urea for Chronic Hyponatremia.

BACKGROUND: Hyponatremia is the most common electrolyte disorder encountered clinically. While acute and/or severe hyponatremia is commonly associated with significant symptoms, milder and more chronic forms of hyponatremia remain clinically inconspicuous. Recent evidence suggests that even milder forms of hyponatremia are associated with increased morbidity and mortality. Despite this, currently available treatments for chronic hyponatremia lack data on efficacy and/or have important limitations related to patient nonadherence, adverse side effects, and/or significant costs. Consequently, there is a clear need for investigation of alternative treatments for this common condition. SUMMARY: Small case series conducted in Europe since the early 1980s suggest that urea, an oral osmotic diuretic that increases urinary water excretion, is safe and effective for the treatment of chronic hyponatremia. In 2016, a novel formulation of urea became available in the United States. Our group recently reported the first and only study describing the efficacy and safety of this American formulation of oral urea among hospitalized patients with hyponatremia. Key Messages: Oral urea appears to be an effective, safe, and well-tolerated therapeutic strategy in the management of chronic hyponatremia.

Treatment of severe symptomatic hyponatremia.

Hyponatremia is the most common electrolyte abnormality seen in the hospital. Severe symptomatic hyponatremia is associated with grave consequences including cerebral edema, brain herniation, seizures, obtundation, coma, and respiratory arrest. However, rapid correction of chronic severe hyponatremia may lead to osmotic demyelination syndrome (ODS) and even death. Given the serious consequences of severe hyponatremia or its inadvertent overcorrection, it is of paramount importance for the clinician to be aware of the various scenarios in which hyponatremic patients can present and tailor the management strategies accordingly. We present here a case of severe hyponatremia of unknown duration with the presenting plasma sodium level of 95 mmol/L and use it to illustrate the various treatment strategies - proactive, reactive, or rescue therapy - along with the physiological basis to support these approaches.

Intravascular Iodinated Contrast Is an Independent Cause of Acute Kidney Injury Following Coronary Angiography.

OBJECTIVES: Recent studies have questioned whether intravascular iodinated contrast remains an independent cause of acute kidney injury (AKI). We sought to assess whether iodinated contrast administered during coronary angiography is an independent cause of AKI. METHODS: We identified all of the patients who underwent coronary angiography between July 1, 2015 and June 30, 2017 with a discharge diagnosis of AKI that developed within 7 days following angiography. Using chart review, we categorized patients as having multifactorial AKI if ≥1 insults other than intravascular contrast potentially contributed to kidney injury or contrast-induced AKI (CI-AKI) if the only insult was contrast administration. We compared the severity of AKI and renal function upon discharge between patients with CI-AKI and multifactorial AKI. RESULTS: We identified 78 patients who experienced AKI within 7 days following angiography, 10 (13%) of whom had CI-AKI and 68 of whom (87%) experienced multifactorial AKI. Nine (90%) patients with CI-AKI manifested stage 1 disease, 1 (10%) had stage 2 disease, and 9 (90%) experienced full recovery of kidney function. More patients with multifactorial AKI developed stage 2 or 3 disease (42% vs 10%, χ2 = 3.73, P = 0.05) and experienced either partial recovery of kidney function or persistent kidney impairment compared with patients with CI-AKI (25% vs 10%, χ2 = 1.9, P = 0.17), although the latter comparison was not statistically significant. CONCLUSIONS: The intravascular administration of iodinated contrast remains an independent cause of AKI. Compared with those with multifactorial AKI, patients with CI-AKI appear to be more likely to experience mild decrements in kidney function that recover completely.