Hyponatremia: Classification and Diagnosis

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HYPONATREMIA: CLASSIFICATION AND DIAGNOSIS

NOAH CARPENTER, MD

Dr. Noah Carpenter is a Thoracic and Peripheral Vascular Surgeon. He completed a Bachelor of Science in chemistry and medical school and training at the University of Manitoba. Dr. Carpenter completed surgical residency and fellowship at the University of Edmonton and Affiliated Hospitals in Edmonton, Alberta, and an additional Adult Cardiovascular and Thoracic Surgery fellowship at the University of Edinburgh, Scotland. He has specialized in microsurgical techniques, vascular endoscopy, laser and laparoscopic surgery in Brandon, Manitoba and Vancouver, British Columbia, Canada and in Colorado, Texas, and California. Dr. Carpenter has an Honorary Doctorate of Law from the University of Calgary, and was appointed a Citizen Ambassador to China, and has served as a member of the Native Physicians Association of Canada, the Canadian College of Health Service Executives, the Science Institute of the Northwest Territories, the Canada Science Council, and the International Society of Endovascular Surgeons, among others. He has been an inspiration to youth, motivating them to understand the importance of achieving higher education.

ABSTRACT

Hyponatremia is the most common disorder of body fluid and electrolyte balance, which can lead to a wide range of clinical symptoms that can be severe or even fatal. Many different conditions can lead to hyponatremia, imposing on health clinicians a high need to recognize the signs and symptoms, and to administer immediate treatment according to the latest medical research and guidelines.

1 NurseCe4Less.com Policy Statement This activity has been planned and implemented in accordance with the policies of NurseCe4Less.com and the continuing nursing education requirements of the American Nurses Credentialing Center's Commission on Accreditation for registered nurses.

Continuing Education Credit Designation This educational activity is credited for 2.5 hours at completion of the activity.

Statement of Learning Need The degree of severity and causes of hyponatremia are often underestimated by health clinicians. Clinicians need to know how to recognize hyponatremia and to distinguish it from false hyponatremia. The conditions that can lead to hyponatremia, how to recognize the conditions, and the proper administration of treatment are important clinical considerations. The latest research and guidelines for recognition and treatment of hyponatremia are key to planning a patient’s course of care.

Course Purpose To provide health clinicians with knowledge of the conditions that can lead to hyponatremia, of how to recognize such conditions, and of the proper treatment.

Target Audience Advanced Practice Registered Nurses, Registered Nurses, and other Interdisciplinary Health Team Members.

Disclosures Noah Carpenter, MD, William Cook, PhD, Douglas Lawrence, MA, Susan DePasquale, MSN, FPMHNP-BC – all have no disclosures. There is no commercial support.

2 NurseCe4Less.com Self-Assessment of Knowledge Pre-Test:

1. Hyponatremia is generally defined as a

a. high or low blood sodium level. b. high calcium concentration. c. low blood sodium level or serum sodium concentration. d. low potassium level.

2. ______hyponatremia is defined as a biochemical finding of a serum sodium concentration <120 mmol/l.

a. Severe b. Moderate c. Pseudo d. Mild

3. ______comprise the majority of patients who are diagnosed with hyponatremia.

a. Males b. Elderly patients c. Adolescents d. Hospitalized patients

4. Acute hyponatremia exists when the condition is documented for a period of

a. a week. b. 72 hours. c. at least 48 hours. d. less than 48 hours.

5. Hyponatremia is classified as ______if a person’s body fluid volume is low.

a. asymptomatic b. euvolemic c. hypervolemic d. hypovolemic

3 NurseCe4Less.com Introduction

Hyponatremia is the most frequent electrolyte disorder encountered by health clinicians. In hospitalized patients, the most common electrolyte disorder is hyponatremia, and the incidence of hyponatremia is significant. It can lead to symptoms that can range from mild to severe, or even fatal. The severity and causes of hyponatremia are often underestimated by health clinicians. The conditions that can lead to hyponatremia, how to recognize the conditions, and the proper administration of treatment are discussed in the following sections. The latest research and guidelines for recognition and treatment of hyponatremia are also raised.

Definition and Etiology of Hyponatremia

Hyponatremia is the most common electrolyte disorder in hospitalized patients associated with increased mortality and morbidity. It is generally defined as a low blood sodium level or serum sodium concentration < 136 mmol/l.1 Mild hyponatremia is defined as a serum sodium concentration between 130 to 134 mEq/L, moderate hyponatremia is defined as a serum sodium concentration between 120 to 129 mEq/L mmol/l, and severe hyponatremia is defined as a serum sodium concentration of < 120 mEq/L.2

The prevalence of hyponatremia is reportedly as high as 30% depending on the criteria for its diagnosis.3 The clinical setting and the patient population are relevant to hyponatremia prevalence, and the condition correlates with significant morbidity and mortality and will vary depending upon the disease states and medical conditions occurring when hyponatremia is diagnosed. Serum sodium levels that are significantly low or fluctuating can lead to serious outcomes, even death.3 Complications of hyponatremia are preventable if the condition is diagnosed early and appropriately treated.

The cause of hyponatremia is important to diagnose correctly. If the etiology is not correctly understood the treatment may lead to worse clinical outcomes. There are multiple causes for decreased serum sodium levels. In patients with a diagnosis of the syndrome of inappropriate antidiuretic

4 NurseCe4Less.com hormone (SIADH) secretion and co-occurring gastrointestinal symptoms, i.e., nausea and vomiting, volume replacement may be a necessary priority of treatment. Clinicians should always keep in mind that the indiscriminate use of large volumes of intravenous normal saline could lead to worsened serum sodium levels in cases of elevated vasopressin levels.3

The incidence of hyponatremia depends in large part on the patient population. Clinical symptoms vary from asymptomatic to seizures and coma. It is important to determine the prevalence of this condition since multiple new drugs exist and there are clinical determinants leading to hyponatremia.3 Moderate-to-severe hyponatremia, in particular with rapid onset, corresponds with significant morbidity and mortality. There are many underlying disease states and multiple causes associated with hyponatremia.3

Individuals who have sodium levels that shift suddenly or are severely hyponatremic must be treated immediately to avoid serious health outcomes and death. Treatment outcomes depends on whether or not the affected person has co-occurring health issues, and the severity of clinical symptoms. A hyponatremic person may be asymptomatic or show severe symptoms, including seizures and coma.3 Medical professionals will need to determine the underlying cause of hyponatremia, such as a clinical condition or medication- induced etiology.

In hospitalized patients the prevalence of hyponatremia has reportedly reached as high as 30% based upon diagnostic criteria, patient population and clinical setting.3 However, in some studies hyponatremia is not found to be as high in hospitalized patients as in earlier reports, which is believed to be due to improved surveillance through laboratory testing of patients on diuretics or drugs known to cause hyponatremia, i.e., those that act on the central nervous system (CNS).3

The elderly, those individuals 65 or greater years of age, comprise the majority of patients who are diagnosed with hyponatremia. Elderly who are prescribed diuretic therapy are at higher risk of becoming hyponatremic.3 However, in younger patients a finding of end stage renal disease (ESRD) was

5 NurseCe4Less.com the primary underlying condition related to the development of hyponatremia. In both elderly and young individuals, hyponatremia is typically a secondary condition.3 Diuretic medication is a well-known cause of hyponatremia therefore patient education of the signs and symptoms of low sodium levels and vigilant monitoring of blood sodium levels, patient fluid intake and conditions that could lead to electrolyte disturbances, such as vomiting and diarrhea, is essential to avoid complications related to hyponatremia.3

Hyponatremia occurs more frequently in females than males.4 People who are depressed and prescribed antidepressant medication, selective serotonin reuptake inhibitors (SSRIs) have been identified with hyponatremia.4 As noted previously, there are multiple factors that can lead to hyponatremia, such as excessive fluid intake.4 Clinicians need to be cautious when diagnosing the cause of hyponatremia and when selecting recommended treatment to prevent a worse complication related to hyponatremia.

Classification of Hyponatremia

A classification system of hyponatremia should be consistent and helpful for both differential diagnosis and treatment. Classification of hyponatremia is according to various factors, and clinicians should recognize that each classification has advantages and disadvantages depending on clinical settings and situations. Clinicians should also bear in mind that differential diagnosis of hyponatremia can be complicated and that combined causes of hyponatremia is possible when diagnosing the condition.

Hyponatremia can be classified according to the status of a person’s body fluid volume as hypovolemic (low volume), hypervolemic (high volume), or euvolemic (normal volume). According to Spasovski, et al. (2014) hyponatremia may be categorized by biochemical severity, time of development, and symptoms.5 This system for diagnosing hyponatremia prioritizes criteria so that classification is clinically relevant and applicable, as must as possible, to a patient’s symptoms.

6 NurseCe4Less.com Nonspecific and Overlapping Symptoms

According to Spasovski and colleagues (2014), a patient can be classified as moderately symptomatic and severely symptomatic.5 The distinction between moderately severe and severe hyponatremia depends on selected observations in acute hyponatremia, such as the degree of brain edema and the extent of immediate danger.5 In this way, the classification of moderate-severe to severe hyponatremia attempts to match treatment to an immediate risk; more aggressive treatment is aimed at more severe symptoms. However, a classification system based on symptom severity alone has its shortcomings. For example, the symptoms of acute and chronic hyponatremia could overlap. A patient who has acute hyponatremia can present with no clear symptoms, and can then develop moderately severe to severe symptoms within hours. Also, symptoms of hyponatremia tend to be nonspecific.

When brain edema causes moderately severe symptoms this is less frequently associated with death.5 However, moderate-severe hyponatremia can rapidly progress to more severe symptoms associated with an adverse outcome. A person who subsequently dies will more often have experienced severe symptoms of hyponatremia.5 Spasovski and colleagues omitted the category of asymptomatic hyponatremia because of the belief that such a classification could create confusion.5 Patients are most likely never truly asymptomatic. Even with mild hyponatremia there are limited and subclinical signs such as mild concentration deficits.

Acute and Chronic Hyponatremia

Hyponatremia may also be described as acute and chronic.5 Acute hyponatremia exists when documented for a period less than 48 hours. Chronic hyponatremia exists when documented for at least 48 hours.5 If the hyponatremia cannot be classified, it is considered chronic unless there is a clinical or anamnestic evidence to the contrary.5

7 NurseCe4Less.com Body Fluid Compartments and Regulation of Sodium

To understand the causes and treatments for hyponatremia clinicians must first have an understanding of the size of body fluid compartments and subcompartments and their regulation. Body cells gain or lose water from the surrounding fluid through a process known as osmosis.6-8 Fluid moves in or out of cells based on the difference in osmotic pressure between the extracellular fluid and the intracellular fluid. The tonicity of the extracellular fluid determines the movement of fluid into or out of a cell. When tension is equal between the cell and surrounding fluid, the solutions are described as isotonic. If surrounding fluid has a greater concentration of a substance, such as sodium, the surrounding fluid is said to be hypertonic, and, if surrounding fluid has a lower concentration of a substance, it is hypotonic.6-8

Under normal circumstances the body can maintain sodium concentrations in a narrow range. The measurement of the amount of a substance that has dissolved in another substance is referred to as osmolality.6-8 For example, if extracellular fluid has a greater concentration of sodium than the cell it surrounds, it is said to have a higher osmolality than the cell. Homeostasis describes a measurement of sodium concentrations in which the body fluid is normal and stable. Conditions can cause feedback systems to malfunction, which lead to consequences. These consequences may impact the size and solute concentration in the fluid compartments.6-8

The hypothalamic-renal feedback system normally maintains the concentration of the serum sodium at a narrow range. In certain cells in the hypothalamus, osmoreceptors respond to an elevated serum sodium in body fluids, signaling the posterior pituitary gland to secrete antidiuretic hormone (ADH), also called vasopressin.8 Antidiuretic hormone enters the bloodstream, signaling the kidneys to bring back sufficient solute free water from the fluid in the kidneys’ tubules, stimulating thirst, moving fluid out of the osmoreceptors (causing them to shrink), and diluting the serum sodium back to normal.

8 NurseCe4Less.com The presence of ADH causes an increase in concentration of aquaporin, a water-transporting protein, in the renal tubule.8 This causes an increase in water absorption to the bloodstream, which leads to the urine retaining higher concentrations of salt and eliminating less water. Normally, when mild hyponatremia begins, serum sodium starts to fall below 135 mEq/L, there is no secretion of ADH (vasopressin); the kidney stops returning water to the body from the renal tubule; and thirst is not stimulated.8 These factors work together to raise serum sodium to a normal range.

Hyponatremia can happen when increased fluid intake overwhelms the hypothalamic/renal feedback loop.8-10 It may also happen when the loop becomes interrupted, which may or may not be related to ADH. It can also happen when the feedback loop malfunctions and ADH is always turned on. When the pores of the kidney are open without receiving a signal from ADH to open this can result in hyponatremia.8-10 Hyponatremia can also occur with increased ADH without a normal stimulus from elevated serum sodium that increases ADH.8-10 A feedback system that is overwhelmed leads to water intoxication. It is associated with very dilute urine. This can be caused by pathological water drinking known as psychotic polydipsia, beer potomania, overzealous intravenous solute free water infusion, or infantile water intoxication.8-10

Impairment of urine dilution related to ADH occurs in a situation of arterial volume depletion, congestive heart failure, hemodynamic mediation, cirrhosis, spinal cord disease, nephrosis, Addison’s disease, cerebral salt wasting, and SIADH.8-10 If the feedback system is normal, impairment of the urine diluting ability unrelated to ADH can be due to oliguric renal failure, diuretics, tubulointerstitial renal disease, or nephrogenic syndrome of antidiuresis.8-10 The primary positively charged ion outside of a cell is sodium and sodium cannot cross from the interstitial space and into the cell due to its size being too large to pass through the cell membrane; a sodium pump or channel is needed.

9 NurseCe4Less.com Common Causes of Hyponatremia

Patients affected by syndrome of inappropriate secretion of antidiuretic hormone may exhibit symptoms of hyponatremia. It is a disorder of impaired water excretion caused by the inability to suppress secretion of antidiuretic hormone. Common causes also include medications.

Hyponatremia can occur in patients with dilute urine and with concentrated urine. When the urine is dilute, the patient can be drinking too much water or other liquids, or can have adrenal insufficiency or hypothyroidism.8-10 When the urine is concentrated, the patient can be affected by SIADH, which leads to hyponatremia that results from an excess of water rather than a deficiency of sodium.8-10

Contributing Factors

With an increase in sodium content, hypervolemia can result, and with an increase in water content, hyponatremia can result. Contributing factors can be liver cirrhosis, nephrotic syndrome, congestive heart failure, and excessive fluid intake.10 With normal volume, there is volume expansion in the body, and there is no edema. When hyponatremia occurs, factors include hypothyroidism and not enough adrenocorticotropic hormone (ACTH).10,11

Low Volume Hyponatremia

Low volume hyponatremia can happen from sweating, diarrhea, diuretics, or vomiting. With low volume, total body sodium loss causes hypovolemia extracellular volume loss. A relatively smaller loss in total body water causes the hyponatremia.10,11

High Volume Hyponatremia

With high volume hyponatremia, both sodium and water content increase. High volume hyponatremia can occur in cases of kidney failure, liver

10 NurseCe4Less.com failure, and heart failure. Too little sodium in the diet is rarely the cause for hyponatremia.10,11

Other factors of hyponatremia are pancreatitis, Addison's disease and congenital adrenal hyperplasia, where the adrenal glands do not produce enough steroid hormones. This is a combined glucocorticoid and mineralocorticoid deficiency.10,11 Another cause can be prolonged periods of exercise. This is known as exercise-associated hyponatremia. This can happen with a marathon runner or anyone involved in another endurance event. The use of the hallucinogenic drug MDMA can also result in hyponatremia. This could happen due to fluid loss as a result of sweating and replacing water without electrolytes. Additional causes could be hyponatremia with normal tonicity and high blood sugar. False hyponatremia can be due to massive increases in blood triglyceride levels or extreme elevation of immunoglobulins as can happen with multiple myeloma.10,11

Symptoms of Hyponatremia

Symptoms of hyponatremia can be subtle, severe, or life-threatening, and should be assessed with caution. Clinicians must be aware that symptoms could be caused by conditions other than hyponatremia, by other conditions in combination with hyponatremia, or by conditions that cause hyponatremia. Clinicians should be particularly careful when attributing moderately severe to severe symptoms to hyponatremia when the condition is only mild.

Acute hyponatremia can include symptoms of neurologic disorder due to cerebral edema caused by water entering the brain. Seizures, impaired mental status or coma and death are possible outcomes of acute hyponatremia.10 On the other hand, chronic hyponatremia develops over 48 hours or longer and individuals with chronic hyponatremia will show serum sodium levels greater than 120 meq/L; the brain adapts by production of idiogenic osmoles, which is a “protective mechanism that reduces the degree of cerebral edema; it begins on the first day and is complete within several days”.10 People with chronic hyponatremia will generally appear asymptomatic.

11 NurseCe4Less.com In mild hyponatremia patients may complain of gastrointestinal tract symptoms nausea, vomiting, loss of appetite. There may be subtle neurologic abnormalities as the serum sodium reaches 120 and 130 meq/L. In elderly individuals, frequent falls and gait disturbances may coincide with hyponatremia.10 Other mild symptoms may include headaches, a decreased ability to think, nausea, and poor balance and severe symptoms can include seizure and coma.10 Symptoms of hyponatremia can include vomiting, nausea, headache, short term memory loss, lethargy, confusion, fatigue, loss of appetite, muscle weakness, irritability, spasms, cramps, seizures, and decreased consciousness or coma.10,11

The severity of hyponatremia symptoms is related to the level of sodium in the blood. Lower levels of plasma sodium correspond with more severe symptoms.10,11 Even mild hyponatremia can include complications and symptoms such as reduced attention and increased falls. When a very low level of plasma sodium develops, water enters the brain cells, causing them to swell and leading to hyponatremic encephalopathy.11-13 Intracranial pressure increases and there is the risk of herniation of the brain. Hyponatremic encephalopathy can result in headaches, vomiting, nausea, confusion, seizures, brain stem compression, and respiratory arrest plus non- cardiogenic accumulation of fluid in the lungs. If not treated immediately, this condition is usually fatal.11,12

The severity of symptoms will depend on the level and speed of the drop of blood sodium. A gradual drop can be tolerated well even if down to very low sodium levels, such as if the drop occurs over several days or weeks. This toleration is due to neuronal adaptation. Severity of neurological symptoms also depends on the presence of an underlying neurological disease.11-12 If hyponatremia is chronic, this can lead to complications of neurological impairments that can affect walking and attention. They can also lead to falls involving an increase in reaction time. Hyponatremia can also interfere with bone metabolism, and has been linked with a doubled risk of osteoporosis. There is also a link to increased risk of bone fracture.11,12

12 NurseCe4Less.com Guidelines for diagnosing hyponatremia include identifying symptoms of low serum sodium that can also be induced by other conditions. Clinicians need to consider the clinical and correlating data when assessing the relationship between hyponatremia and a particular symptom. A symptom should be assessed as to whether it was caused by hyponatremia or whether hyponatremia was caused by the underlying condition or symptom. The less pronounced or mild the degree of hyponatremia, the more cautious clinicians should be about considering hyponatremia as the cause of symptoms.11,12 All symptoms of hyponatremia can be considered severe or moderate and involve a level of cerebral edema. Symptoms for moderately severe hyponatremia is nausea without vomiting, confusion, and headache. Symptoms for severe hyponatremia is vomiting, cardiorespiratory distress, abnormal and deep somnolence, seizures, and coma.11,12

Diagnosis of Hyponatremia

While hyponatremia is the most frequent electrolyte disorder, it is SIADH that accounts for about one-third of hyponatremia cases. When diagnosing SIADH it is important to determine the euvolemic state of extracellular fluid volume. This is true both clinically and by laboratory measurement.12-14 Inappropriate treatment of hyponatremia, mainly over- treatment, can lead to a devastating outcome. Under-treatment is less frequent but it can also lead to devastating outcomes. Of great importance is the appropriate diagnosis of the cause of hyponatremia, proper management and treatment.

One pitfall in evaluating a patient with hyponatremia is the failure to exclude pseudo-hyponatremia or hypertonic hyponatremia as related to glucose, glycine, or mannitol.12-14 Proper assessment of urine sodium concentration and other lab findings and diagnosis of other causes of hyponatremia are important, including cerebral salt wasting, reset osmostat, nephrogenic syndrome of inappropriate antidiuresis, prolonged strenuous exercise, and drug use. The typical pitfalls of diagnosing hyponatremia could endanger a patient’s life, and are highlighted in the remainder of this section.

13 NurseCe4Less.com False Hyponatremia

The condition of false hyponatremia is also known as pseudo, spurious, hypertonic, and artifactual hyponatremia. It occurs when a laboratory test shows a reading of low sodium levels; however, with this reading, there is no hypotonicity. Some conditions, such as high blood protein levels as with high blood sugar levels, multiple myeloma, or high blood fat levels can lead to a false measurement of low sodium.13,14

Diagnostic Criteria for SIADH

The diagnostic criteria for Syndrome of inappropriate antidiuretic hormone secretion (SIADH) include:14 ● Effective serum osmolality < 275 mOsm/kg ● Urine osmolality > 100 mOsm/kg at some level of decreased effective osmolality ● Clinical euvolemia ● Urine sodium concentration > 30 mmol/l with normal dietary salt and water intake ● Absence of adrenal, thyroid, pituitary, or renal insufficiency ● No recent use of diuretic agents

The supplemental criteria for SIADH include:14 ● Serum uric acid < 0.24 mmol/l (< 4 mg/dl) ● Serum urea < 3.6 mmol/l (< 21.6 mg/dl) ● Failure to correct hyponatremia after 0.9 percent saline infusion ● Fractional sodium excretion > 0.5 percent ● Fractional urea excretion > 55 percent ● Fractional uric acid excretion > 12 percent ● Correction of hyponatremia through fluid restriction

Differentiating Causes of Hypotonic Hyponatremia

Parameters recommended for differentiating causes of hypotonic hyponatremia include, as a first step, interpreting the urine osmolality of a

14 NurseCe4Less.com spot urine sample.14 If urine osmolality is less than or equal to 100 mOsm/kg, accept relative excess water intake as a cause of hypotonic hyponatremia; and, if urine osmolality is > 100 mOsm/kg, interpret the urine sodium concentration on a spot urine test sample taken simultaneously with a blood sample.14

For a urine sodium concentration less than or equal to 30 mmol/l, low effective arterial volume should be considered as a cause of hypotonic hyponatremia.14 A urine sodium concentration greater than 30 mmol/l, should lead the medical clinician to address extracellular fluid status and use of diuretics to further differentiate the likely causes of hyponatremia. Vasopressin should not be measured to confirm the diagnosis of SIADH.14

Hypotonic and Non-hypotonic Hyponatremia

Confirming hypotonic and excluding non-hypotonic hyponatremia should include the following considerations and steps: 1) Exclude hyperglycemic hyponatremia by measuring the serum glucose concentration and correcting the measured serum sodium concentration for the serum glucose concentration if it is increased, 2) Consider that hyponatremia with a measured osmolality < 275 mOsm/kg always reflects hypotonic hyponatremia, and 3) Accept hypotonic hyponatremia as hyponatremia without evidence of non-hypotonic hyponatremia.14 Causes of non-hypotonic hyponatremia include the following settings and examples.14

The presence of effective osmoles raise serum osmolality and can cause hyponatremia, which include glucose, mannitol, glycine, histidine- tryptophan-ketoglutarate, hyperosmolar radiocontrast media, and maltose.14 Also, ineffective osmoles that raise serum osmolality but do not cause hyponatremia, which include urea, alcohols, and ethylene glycol, should be monitored.14 The presence of endogenous solutes that cause pseudohyponatremia (laboratory artifact) include triglycerides, cholesterol, and protein, intravenous immunoglobulins, and monoclonal gammopathies.14

15 NurseCe4Less.com Clinical Assessment of Fluid Status

Two studies are reported by Spaskovski and colleagues to indicate that in patients with hyponatremia, clinical assessment of volume status has low sensitivity and specificity. Low sensitivity is 0.5 to 0.8 and specificity is 0.3 - 0.5.14 It was also noted that it seems clinicians often misclassify hyponatremia when “using algorithms that start with a clinical assessment of volume status. Using an algorithm in which urine osmolality and urine sodium concentration are prioritized over assessment of volume status, physicians in training had a better diagnostic performance than senior physicians who did not use the algorithm.”14

Urine Osmolality

For the evaluation of hyponatremia, urine osmolality is used. Recommendations include:14 ● As a first step, interpret urine osmolality of a spot urine sample. ● If urine osmolality is less than or equal to 100 mOsm/kg, accept relative excess water intake as a cause of hypotonic hyponatremia. ● If urine osmolality is > 100 mOsm/kg, interpret the urine sodium concentration on a spot urine test sample taken simultaneously with a blood sample. ● If urine sodium concentration is less than or equal to 30 mmol/l, accept low effective arterial volume as a cause of hypotonic hyponatremia. ● If urine sodium concentration is greater than 30 mmol/l, address extracellular fluid status and use of diuretics to further differentiate the likely causes of hyponatremia. ● Do not measure vasopressin for confirming the diagnosis of SIADH.

Advice for clinical practice includes:14 ● Contemporaneous collection of blood and urine sample are required for correct interpretation of laboratory measurements. ● Use the same urine sample to determine urine osmolality and sodium concentration as this is best for practical reasons.

16 NurseCe4Less.com ● If a clinical assessment shows the volume of extracellular fluid is not overtly increased and urine sodium concentration is > 30 mmol/l, exclude other causes of hypotonic hyponatremia before implicating syndrome of inappropriate diuresis (SIAD). Consider using the diagnostic criteria and search for known causes of SIAD. ● Consider primary or secondary adrenal insufficiency to assess vasopressin activity.

Urine Sodium Concentration

Five studies exist that assess diagnostic accuracy of urine sodium concentration for differentiating hypovolemia from euvolemic or hypervolemia. Spasovski and colleagues noted that “all studies used a rise in serum sodium concentration after the infusion of 0.9% sodium chloride as the reference standard for diagnosing hypovolemia ... Four studies assessed the sensitivity and specificity of a urine sodium concentration > 30 mmol/l for diagnosis of euvolemia versus hypovolemia ... All found similarly high sensitivity estimates ranging from 0.87 to 1.0 but variable specificity estimates ranging from 0.52 to 0.83 ... Fenske, et al. also included hypervolemic patients. They assessed the same threshold for distinguishing hypovolemia from euvolemia and hypervolemia, but analyzed patients with and without diuretics separately... A urine sodium concentration > 30 mmol/l had high estimated sensitivities of 1.0 and 0.94 respectively in patients off and on diuretics, but low specificities of 0.69 and 0.24 respectively.”14 Others evaluated the diagnostic accuracy of a urine sodium concentration > 50 mmol/l and > 20 mmol/l but found lower sensitivities and specificities respectively than with a threshold of > 30 mmol/l.14

Other Laboratory Tests

Other diagnostic lab tests distinguish euvolemia from hypovolemia and hypervolemia in patients treated with and without diuretics, and include:14 ● Serum urea concentration ● Serum uric acid concentration ● Fractional sodium excretion

17 NurseCe4Less.com ● Fractional uric acid excretion ● Fractional urea excretion ● Plasma copeptin concentration

Fractional excretion of uric acid using a threshold of > 12% seemed most useful for distinguishing hyponatremia due to SIAD from non-SIAD hyponatremia.14 This is in patients under diuretics with a sensitivity of 0.86 and specificity of 1.0. In comparison with urine sodium concentration, fractional uric acid excretion may be a better test for differentiating hyponatremia in patients who are also treated with diuretic therapy and these results need to be confirmed in a separate cohort before this parameter can be recommended for routine use clinically.14

Diuretics and Diagnosis

Diagnostic difficulty occurs in the setting of diuretic use. Patients on diuretic medications can have increased, normal or decreased extracellular and circulating volume. These patients can also have increased or decreased urine sodium concentration, depending on the timing of the most recent tablet, irrespective of their underlying volume status.14 The natriuresis induced by diuretics may cause ‘appropriate’ vasopressin release. It can also cause subsequent hyponatremia because of a decrease in circulating volume. Diuretics can cause a SIAD-like state characterized by normal or mildly increased extracellular fluid volume. Urine sodium concentration could also be low in a patient with heart failure or liver cirrhosis due to reduced effective circulating arterial volume, even when they are taking diuretics.14

The diagnosis of hyponatremia depends on the underlying cause and is an important step to proper treatment. However, correcting the condition too rapidly can result in complications.14,15 A rapid partial correction of hyponatremia with 3% normal saline is recommended only for those with significant symptoms and on occasion for those who have been diagnosed with rapid onset of hyponatremia.14,15 For low volume hyponatremia the typical treatment is intravenous normal saline, for SIADH the typical treatment is fluid restriction, and for high volume hyponatremia both fluid restriction and

18 NurseCe4Less.com a diet low in salt are typically pursued. Those who have low levels for more than two days should generally receive gradual correction.14,15

Hyponatraemia can be life threatening, however chronic hyponatremia, even when it is profound, generally can be well tolerated by affected individuals. When the brain has adapted to a state of chronic hyponatremia the rapid correction of hyponatremia includes a risk of significant neuronal osmolar stress and life threatening osmotic demyelination within the central nervous system.15 Therefore, taking a stratified approach is recommended, which includes “balancing the severity of the clinical situation, the efficacy and potential adverse effects of intervention, and the impact of persisting hyponatraemia.”15

Case Study: Euvolemic Hyponatremia

The following case study was located through a PubMed search and the authors reported on a 69-year-old man who arrived at hospital with complaints of general weakness and fever.16

The patient’s health history indicated that he had been treated with numerous medications: an angiotensin-converting enzyme (ACE) inhibitor, metformin, a DPP-IV inhibitor, and thioctacid, for management of hypertension and type 2 diabetes mellitus. Several weeks prior to hospital admission, it was noted that the patient had developed a severe right heel ulcer due to arteriosclerosis obliterans. Pregabalin was started for the relief of the right heel pain.

A physical assessment of the patient on admission revealed his blood pressure to be 128/58 mmHg, pulse rate 76 beats per minute, and the body temperature 37.8 °C. There were audible crackles over both lung fields. There was no neurologic deficits or other abnormal symptoms with the exception of an appearance of mild shortness of breath.

Laboratory testing was done and the patient’s blood workup included a complete blood count with a slightly elevated white blood cell count of

19 NurseCe4Less.com 11,150/mm3 (reference range, 400-10,000/mm3), and a low hemoglobin level of 9.6 g/dL (reference range, 13-17.5 g/dL). The blood chemistry included a test of the sodium level, which was normal at 138 mEq/L (reference range, 136-145 mEq/L) and a normal potassium level of 5.0 mEq/L (reference range, 3.5-5.1 mEq/L). The liver function tests and renal function tests were normal.

Consolidation of both lower lobes of the lungs was confirmed by computed tomography (CT) and the patient was diagnosed with pneumonia. A course of ceftriaxone and clarithromycin was administered as proper treatment for pneumonia and stopped after 2 weeks as the patient's condition had improved. Following discontinuation of pneumonia treatment, the patient was reportedly hyponatremic (sodium level 122 mEq/L). Serum sodium level continued to decrease to 118 mEq/L. A chest radiography revealed the patient’s pneumonia had improved. Endocrinologic studies were done in the setting of hyponatremia to exclude conditions of hypothyroidism and adrenal insufficiency. Further laboratory studies showed a reduced serum osmolality (249 mOsm/kg) and random spot urine sodium and osmolality levels were 91 mEq/L (reference range, 40-220 mEq/L) and 451 mOsm/kg (reference range, 300-900 mOsm/kg), respectively.

Syndrome of inappropriate antidiuretic hormone secretion was diagnosed based on the finding of clinical euvolemia and the biochemical data. With the exception of antibiotic therapy for pneumonia the patient received no other medication. The patient was started on fluid restriction, however the serum sodium level remained uncorrected. The authors reported that 3% saline was administered, however the serum sodium level returned as 116 mEq/L. A referral was made to the nephrology clinic for evaluation of SIADH and to determine proper course of treatment.

Thyroid and adrenal function testing was done that were unremarkable. It was determined that SIADH may have been pregabalin-induced and therefore it was stopped. Surveillance of the serum sodium and urine osmolality continued and the patient was given 0.9% isotonic saline. Following pregabalin discontinuation, the serum sodium level increased to 121 mEq/L

20 NurseCe4Less.com with a decreased urine osmolality of 389 mEq/L. The serum sodium level increased to a near-normal level of 130 mEq/L after another two days. Following discontinuation of pregabalin the patient remained asymptomatic and further laboratory testing of the patient’s blood chemistry improved after stopping pregabalin therapy.

Discussion16

The authors stated that drug-induced SIADH “can occur owing to an increased sensitivity to ADH in the nephron or an increase in ADH production.”16 They further stated that an increase of “ADH activity impairs the ability of the kidney to dilute urine, resulting in decreased excretion of ingested water and a highly concentrated and decreased urine volume.”16 Syndrome of inappropriate antidiuretic hormone secretion includes a euvolemic status since excess water will distribute evenly throughout the body's fluid compartments.16

Selective serotonin reuptake inhibitors (SSRIs), various chemotherapeutic agents (cyclophosphamide, cisplatin, and vinca alkaloids), carbamazepine, and antipsychotics are reportedly strongly associated with drug-induced SIADH. Pregabalin “is an analog of the neurotransmitter gamma-aminobutyric acid (GABA) that has analgesic, anticonvulsant, and anxiolytic properties. It is now widely used in the management of diabetic peripheral neuropathy, post-herpetic neuralgia, generalized anxiety disorder, and social anxiety disorder.”16 The authors reported that the most common adverse events associated with pregabalin use are dizziness and somnolence, peripheral edema and weight gain, whereas hyponatremia is an uncommon side effect of pregabalin.

Pregabalin is a first-line treatment for neuropathic pain. Other recommended treatments include tricyclic antidepressants (TCA), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRI). The authors stated that the TCAs, SSRIs, and SNRIs contribute to the development of SIADH. They considered that pregabalin may have this same effect and therefore stopped it. The authors raised that

21 NurseCe4Less.com pregabalin-induced SIADH occurs but is not very frequently reported due to the fact that patients are asymptomatic or present with mild hyponatremia. Pregabalin-induced SIADH could be hard to detect without proper laboratory testing. Prior studies showed a correlation between pregabalin use and symptomatic chronic heart failure, edema, and weight gain. Following discontinuation of pregabalin the symptoms of heart failure resolved.

In considering the research and prior studies, the authors discussed that the calcium channel relationship of pregabalin is believed to cause side effects of heart failure. While pregabalin had analgesic, anticonvulsant, and anxiolytic activity, the drug’s alpha2-delta type 1 and 2 subunits effects on calcium channel functions and conventional calcium channel subtypes was also thought to lead to peripheral edema with peripheral vasodilation and fluid leakage into the interstitial space. Unexplained weight gain could indicate fluid retention and worsen the condition of congestive heart failure. The authors additionally noted that SIADH can develop as a result of fluid leakage into the interstitial space and fluid retention.16

Drug-induced SIADH has been reported for many drugs however the authors stated that pregabalin-induced SIADH is rarely reported. They noted only two prior cases where hyponatremia developed. In one patient hyponatremia occurred two weeks following initiation of pregabalin 75 mg once daily for neuropathic pain and in a type II diabetic patient with nephropathy, neuropathy, and ischemic cardiomyopathy with congestive heart failure (left ventricular function, 27%) the patient developed disorientation secondary to hyponatremia just one week after pregabalin had been started. In both cases the hyponatremia improved after pregabalin was discontinued. The authors summarized by noting that hyponatremia should be considered and closely monitored when initiating pregabalin therapy. In addition, it is important for clinicians to suspect the drug as a potential cause of hyponatremia even though pregabalin-induced SIADH is not commonly reported.

22 NurseCe4Less.com Summary

Hyponatremia can be classified according to the status of a person’s body fluid volume as hypovolemic (low volume), hypervolemic (high volume), or euvolemic (normal volume). According to Spasovski and colleagues hyponatremia may be categorized by biochemical severity, time of development, and symptoms. The system for diagnosing hyponatremia prioritizes criteria so that classification is clinically relevant and as applicable as possible to a patient’s symptoms.

One pitfall in evaluating a patient with hyponatremia is the failure to exclude pseudo-hyponatremia or hypertonic hyponatremia as related to glucose, glycine, or mannitol. Proper assessment of urine sodium concentration and other lab findings and diagnosis of other causes of hyponatremia are important, including cerebral salt wasting, reset osmostat, nephrogenic syndrome of inappropriate antidiuresis, prolonged strenuous exercise, and drug use. The typical pitfalls of diagnosing hyponatremia could endanger a patient’s life.

23 NurseCe4Less.com The syndrome of inappropriate antidiuretic hormone secretion is the most common cause of euvolemic hyponatremia and causes of SIADH, including medication induced euvolemic hyponatremia was discussed. Several drugs are known to cause SIADH, and some are rarely reported, such as in the case study presented on pregabalin-induced hyponatremia. In the absence of other causes, medical providers should consider stopping a drug with the potential to cause hyponatremia and vigilantly monitor the clinical course and laboratory trends during a patient’s course of care.

24 NurseCe4Less.com Self-Assessment of Knowledge Post Test:

Please take time to help NurseCe4Less.com course planners evaluate the nursing knowledge needs met by completing the self-assessment of Knowledge Questions after reading the article, and providing feedback in the online course evaluation. Completing the study questions is optional and is NOT a course requirement.

1. Hyponatremia is generally defined as a

a. high or low blood sodium level. b. high calcium concentration. c. low blood sodium level or serum sodium concentration. d. low potassium level.

2. ______hyponatremia is defined as a biochemical finding of a serum sodium concentration <120 mmol/l.

a. Severe b. Moderate c. Pseudo d. Mild

3. ______comprise the majority of patients who are diagnosed with hyponatremia.

a. Males b. Elderly patients c. Adolescents d. Hospitalized patients

4. Acute hyponatremia exists when the condition is documented for a period of

a. a week. b. 72 hours. c. at least 48 hours. d. less than 48 hours.

25 NurseCe4Less.com 5. Hyponatremia is classified as ______if a person’s body fluid volume is low.

a. asymptomatic b. euvolemic c. hypervolemic d. hypovolemic

6. True or False: Hyponatremia is often classified as asymptomatic hyponatremia because most patients are likely to have no symptoms associated with hyponatremia.

a. True b. False

7. If extracellular fluid has a greater concentration of a substance (e.g., sodium) than the cell it surrounds, the extracellular fluid is said to be

a. hypertonic. b. hypotonic. c. hyperbolic. d. isotonic.

8. The hypothalamus responds to an elevated serum sodium in body fluids by

a. stimulating the sweat glands. b. stopping the return of water to the body from the kidneys. c. stimulating thirst. d. blocking the secretion of vasopressin.

9. True or False: The primary positively charged ion outside of a body’s cell is sodium.

a. True b. False

26 NurseCe4Less.com 10. Normally, when mild hyponatremia begins, serum sodium starts to fall below 135 mEq/L and

a. antidiuretic hormone (ADH) is secreted. b. the kidney returns water to the body from the renal tubule. c. thirst is stimulated. d. vasopressin is not secreted.

11. ______can be caused by pathological water drinking known as psychotic polydipsia.

a. Urine osmolality b. Chronic hyponatremia c. Water intoxication d. Concentrated urine

12. Which of the following conditions, which is unrelated to the role of antidiuretic hormone (ADH), can impair the urine’s diluting ability?

a. Addison’s disease b. SIADH c. Diabetes insipidus d. Oliguric renal failure

13. When the urine is concentrated, the patient can be affected by ______, which leads to hyponatremia that results from an excess of water rather than a deficiency of sodium.

a. Hypothyroidism b. SIADH c. Addison’s disease d. Oliguric renal failure

14. Low volume hyponatremia can be caused by

a. an increase in both sodium and water. b. too little sodium in the diet. c. diuretics. d. kidney failure.

27 NurseCe4Less.com 15. The severity of hyponatremia symptoms increase

a. if there is an increase in both sodium and water. b. as plasma sodium levels drop. c. in patients with high-sodium diets. d. in cases of hypertonic hyponatremia.

16. True or False: Proper assessment of other causes of hyponatremia are important, including prolonged strenuous exercise.

a. True b. False

17. ______may lead to a false diagnosis of hyponatremia.

a. High blood protein levels b. High blood fat levels c. Multiple myeloma d. All of the above

18. The presence of effective osmoles that raise serum osmolality, which can cause hyponatremia, include

a. urea. b. ethylene glycol. c. glucose. d. alcohols.

19. Patients on diuretics may have ______extracellular and circulating volume.

a. increased b. normal c. decreased d. All of the above

20. True or False: Do not use the same urine sample to determine urine osmolality and sodium concentration.

a. True b. False

28 NurseCe4Less.com CORRECT ANSWERS:

1. Hyponatremia is generally defined as a

c. low blood sodium level or serum sodium concentration.

“It is generally defined as a low blood sodium level or serum sodium concentration < 136 mmol/l.”

2. ______hyponatremia is defined as a biochemical finding of a serum sodium concentration <120 mmol/l.

a. Severe

“Mild hyponatremia is defined as a serum sodium concentration between 130 to 134 mEq/L, moderate hyponatremia is defined as a serum sodium concentration between 120 to 129 mEq/L mmol/l, and severe hyponatremia is defined as a serum sodium concentration of < 120 mEq/L.”

3. ______comprise the majority of patients who are diagnosed with hyponatremia. b. Elderly patients

“In hospitalized patients the prevalence of hyponatremia has reportedly reached as high as 30% based upon diagnostic criteria, patient population and clinical setting. However, in some studies hyponatremia is not found to be as high in hospitalized patients as in earlier reports, .... The elderly, those individuals 65 or greater years of age, comprise the majority of patients who are diagnosed with hyponatremia. Hyponatremia occurs more frequently in females than males.”

4. Acute hyponatremia exists when the condition is documented for a period of

d. less than 48 hours.

“Acute hyponatremia exists when documented for a period less than 48 hours. Chronic hyponatremia exists when documented for at least 48 hours. If the hyponatremia cannot be classified, it is considered chronic unless there is a clinical or anamnestic evidence to the contrary.”

29 NurseCe4Less.com 5. Hyponatremia is classified as ______if a person’s body fluid volume is low.

d. hypovolemic

“Hyponatremia can be classified according to the status of a person’s body fluid volume as hypovolemic (low volume), ...”

6. True or False: Hyponatremia is often classified as asymptomatic hyponatremia because most patients are likely to have no symptoms associated with hyponatremia.

b. False

“Spasovski and colleagues omitted the category of asymptomatic hyponatremia because of the belief that such a classification could create confusion. Patients are most likely never truly asymptomatic.”

7. If extracellular fluid has a greater concentration of a substance (e.g., sodium) than the cell it surrounds, the extracellular fluid is said to be

a. hypertonic.

“The tonicity of the extracellular fluid determines the movement of fluid into or out of a cell. When tension is equal between the cell and surrounding fluid, the solutions are described as isotonic. If surrounding fluid has a greater concentration of a substance, such as sodium, the surrounding fluid is said to be hypertonic, and, if surrounding fluid has a lower concentration of a substance, it is hypotonic.”

8. The hypothalamus responds to an elevated serum sodium in body fluids by

c. stimulating thirst.

“In certain cells in the hypothalamus, osmoreceptors respond to an elevated serum sodium in body fluids, signaling the posterior pituitary gland to secrete antidiuretic hormone (ADH), also called vasopressin. Antidiuretic hormone enters the bloodstream, signaling the kidneys to bring back sufficient solute free water from the fluid in the kidneys’ tubules, stimulating thirst, moving fluid out of the osmoreceptors (causing them to shrink), and diluting the serum sodium back to normal.”

30 NurseCe4Less.com 9. True or False: The primary positively charged ion outside of a body’s cell is sodium.

a. True

“The primary positively charged ion outside of a cell is sodium.”

10. Normally, when mild hyponatremia begins, serum sodium starts to fall below 135 mEq/L and

d. vasopressin is not secreted.

“Normally, when mild hyponatremia begins, serum sodium starts to fall below 135 mEq/L, there is no secretion of ADH (vasopressin); the kidney stops returning water to the body from the renal tubule; and thirst is not stimulated. These factors work together to raise serum sodium to a normal range.”

11. ______can be caused by pathological water drinking known as psychotic polydipsia.

c. Water intoxication

“A feedback system that is overwhelmed leads to water intoxication. It is associated with very dilute urine. This can be caused by pathological water drinking known as psychotic polydipsia, beer potomania, overzealous intravenous solute free water infusion, or infantile water intoxication.”

12. Which of the following conditions, which is unrelated to the role of antidiuretic hormone (ADH), can impair the urine’s diluting ability?

d. Oliguric renal failure

“If the feedback system is normal, impairment of the urine diluting ability unrelated to ADH can be due to oliguric renal failure, diuretics, tubulointerstitial renal disease, or nephrogenic syndrome of antidiuresis. The primary positively charged ion outside of a cell is sodium and sodium cannot cross from the interstitial space and into the cell due to its size being too large to pass through the cell membrane; a sodium pump or channel is needed.”

31 NurseCe4Less.com 13. When the urine is concentrated, the patient can be affected by ______, which leads to hyponatremia that results from an excess of water rather than a deficiency of sodium.

b. SIADH

“Hyponatremia can occur in patients with dilute urine and with concentrated urine. When the urine is dilute, the patient can be drinking too much water or other liquids, or can have adrenal insufficiency or hypothyroidism. When the urine is concentrated, the patient can be affected by SIADH, which leads to hyponatremia that results from an excess of water rather than a deficiency of sodium.”

14. Low volume hyponatremia can be caused by

c. diuretics.

“Low volume hyponatremia can happen from sweating, diarrhea, diuretics, or vomiting…. With high volume hyponatremia, both sodium and water content increase. High volume hyponatremia can occur in cases of kidney failure, liver failure, and heart failure. Too little sodium in the diet is rarely the cause for hyponatremia.”

15. The severity of hyponatremia symptoms increase

b. as plasma sodium levels drop.

“The severity of hyponatremia symptoms is related to the level of sodium in the blood. Lower levels of plasma sodium correspond with more severe symptoms.”

16. True or False: Proper assessment of other causes of hyponatremia are important, including prolonged strenuous exercise.

a. True

“Proper assessment of urine sodium concentration and other lab findings and diagnosis of other causes of hyponatremia are important, including cerebral salt wasting, reset osmostat, nephrogenic syndrome of inappropriate antidiuresis, prolonged strenuous exercise, and drug use.”

32 NurseCe4Less.com 17. ______may lead to a false diagnosis of hyponatremia.

a. High blood protein levels b. High blood fat levels c. Multiple myeloma d. All of the above [correct answer]

“The condition of false hyponatremia is also known as pseudo, spurious, hypertonic, and artifactual hyponatremia. It occurs when a laboratory test shows a reading of low sodium levels; however, with this reading, there is no hypotonicity. Some conditions, such as high blood protein levels as with high blood sugar levels, multiple myeloma, or high blood fat levels can lead to a false measurement of low sodium.”

18. The presence of effective osmoles that raise serum osmolality, can cause hyponatremia, include

c. glucose.

“The presence of effective osmoles raise serum osmolality and can cause hyponatremia, which include glucose, mannitol, glycine, histidine- tryptophan-ketoglutarate, hyperosmolar radiocontrast media, and maltose.”

19. Patients on diuretics may have ______extracellular and circulating volume. a. increased b. normal c. decreased d. All of the above [correct answer]

“Diagnostic difficulty occurs in the setting of diuretic use. Patients on diuretic medications can have increased, normal or decreased extracellular and circulating volume.”

20. True or False: Do not use the same urine sample to determine urine osmolality and sodium concentration.

b. False

“Use the same urine sample to determine urine osmolality and sodium concentration as this is best for practical reasons.”

33 NurseCe4Less.com References Section

The References below include published works and in-text citations of published works that are intended as helpful material for further reading.

1. Lewis, J. Hyponatremia. Merck Manual Professional Version. 2018; Retrieved from https://www.merckmanuals.com/professional/endocrine-and- metabolic-disorders/electrolyte- disorders/hyponatremia?query=hyponatremia 2. Sterns, R. Overview of the treatment of hyponatremia in adults. UpToDate. 2019; Retrieved from https://www.uptodate.com/contents/overview-of-the-treatment-of- hyponatremia-in- adults?search=hyponatremia&source=search_result&selectedTitle=1~ 150&usage_type=default&display_rank=1 3. Win, S, et al. Current Trends in Prevalence and Etiologic Factors Responsible for Hyponatremia in Hospitalized Patients. Journal of Nephrology & Therapeutics; 2016; 6:6 DOI: 10.4172/2161- 0959.1000279 4. Mayo Clinic. Hyponatremia. Mayo Staff. 2019; Retrieved from https://www.mayoclinic.org/diseases- conditions/hyponatremia/symptoms-causes/syc-20373711 5. Spasovski, G., et al. Clinical practice guideline on diagnosis and treatment of hyponatremia. 2014; Eur J Endocrinol 170 G1-G47. 6. Lee, J., et al. Management of hyponatremia. CMAJ: Canadian Medical Association Journal. 2014; 186(8). 7. Lewis, J. Hyponatremia. Merck Manual Professional Version. 2018; Retrieved from https://www.merckmanuals.com/professional/endocrine-and- metabolic-disorders/electrolyte- disorders/hyponatremia?query=hyponatremia 8. Sterns, R. Overview of the treatment of hyponatremia in adults. UpToDate. 2019; Retrieved from https://www.uptodate.com/contents/overview-of-the-treatment-of- hyponatremia-in- adults?search=hypertonic&source=search_result&selectedTitle=2~150 &usage_type=default&display_rank=2 9. Rana, R, Saravanan, A, Nizar, H. Assessment of Hyponatremia in Acute Medical Patients. Ulster Med J. 2019; 88(1): 58–59. 10. Sahay, M and Sahay, R. Hyponatremia: A practical approach. Indian J Endocrinol Metab. 2014; (6): 760–771.

34 NurseCe4Less.com 11. Weismann, D, Schneider, A, Hoybe, C. Clinical aspects of symptomatic hyponatremia. Endocr Connect. 2016; 5(5): R35–R43. 12. Williams, D., et al. The clinical management of hyponatraemia. Postgraduate Medical Journal. 2016; 92 (1089): 407–11. 13. Filippatos, T., et al. Ten common pitfalls in the evaluation of patients with hyponatremia. European Journal of Internal Medicine. 2016; 29: 22–25. 14. Spasovski, G., et al. Clinical practice guideline on diagnosis and treatment of hyponatremia. Eur J Endocrinol; 2014; 170 G1-G47. 15. Ball, SG. How I approach hyponatremia. Clinical Medicine. 2013; Vol 13, No 3: 291–5 16. Jung, YJ, et al. A Case Report of Syndrome of Inappropriate Antidiuretic Hormone Induced by Pregabalin. Electrolyte Blood Press. 2016; 14(2): 31–34.

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