Introduction

Osmolality indicates the concentration of all the particles dissolved in body fluid. It is routinely measured in clinical laboratories for the differential diagnosis of disorders related to hydrolytic balance regulation, renal function, and small-molecule poisonings.[1] Serum and urine osmolality tests are usually measured together to be compared and reach the diagnosis of any disease that influences osmolality. Serum osmolality is affected by the concentration of blood chemicals like chloride, sodium (Na), proteins, bicarbonate, and glucose. The blood urea nitrogen (BUN) measurement is important for calculating serum osmolality. Specific therapies and toxins that affect an individual’s fluid balance should also be evaluated with serum osmolality.

The 1975 Dorwart and Chalmers formula, serum osmolality = 1.86(Na) + (glucose/18) + (BUN/2.8) + 9, had been often used to calculate plasma osmolality.[2] In 1976, Smithline and Gardner proposed to use serum osmolality = 2(Na) + glucose/18 + BUN/2.8 as a simpler formula.[3] In 1987, Worthley et al. concluded that the best formula was the simple Smithline-Gardner formula, where the plasma concentrations are measured in mmol/l.[4] Many other formulas have been developed and used over the years, but the simple Smithline-Gardner formula remains the most useful.[5][6] Some authors argue that the formula 1.86(Na+K)+1.15(Glu/18)+(Urea/6)+14 is the most precise of them.[7]

The normal serum osmolality should range from 275 to 295 mOsm/kg.[2][8] Water normally flows from the compartment of low osmolality to the compartment of high osmolality; this only occurs if the membrane between the two compartments is permeable to water. When water moves between plasma and intracellular compartments, the movement direction depends on both compartments' osmolalities. For example, if a cell is in a relatively hyperosmolar solution, fluid will move out of the cell towards the highly concentrated compartment to reach homeostasis. As a result, the cell will shrink.

Pathophysiology

Low Serum Osmolality (Hypoosmolar Serum)

Psychogenic polydipsia: A psychiatric condition characterized by self-induced water intoxication. The disease process has three phases. First, polyuria and polydipsia, followed by the second phase, as the kidney cannot excrete the excess water, resulting in hypoosmolar plasma that manifests as hyponatremia. The final phase is water intoxication, manifesting as delirium, ataxia, nausea, seizures, and vomiting, which may ultimately be fatal.[9]

Syndrome of inappropriate antidiuretic hormone (SIADH): The condition occurs when the body produces an excessive amount of antidiuretic hormone (ADH) due to multiple causes, such as central nervous system tumors, medications, and lung cancers, resulting in the kidneys reabsorbing too much water, which manifests as a dilutional hypoosmolar plasma and hypertension. The treatment can involve medications that block the vasopressin receptor, such as tolvaptan, therapy with hypertonic saline, removing the medications inducing SIADH, or treating the primary cause.[10]

Nephrotic syndrome: A general term that describes the disease processes which result in excessive loss of protein in the urine (proteinuria over 3 grams/day), accompanied by hypertriglyceridemia, hypoalbuminemia, and a hypercoagulable state. The proteinuria occurs when there is damage to the podocyte foot processes or the glomerular basement membrane, which results in decreased serum osmolality and oncotic pressure.[11]

Liver cirrhosis: Albumin is produced by the liver and then secreted out of the hepatic cells into the extravascular space, then returned to the blood via the lymphatic system. When liver damage occurs, the body is unable to produce albumin, which results in a hypoosmolar serum.[12]

High Serum Osmolality (Hyperosmolar Serum)

Diabetes insipidus (DI): This disease is manifested by the excretion of a large volume of urine; this will result in hyperosmolar plasma (greater than 300 mOsm/liter) and hypoosmolar urine (less than 300 mOsm/liter). It can result from a lack of ADH (central) due to damage to the neurons responsible for ADH production secondary to pituitary/hypothalamic infarcts, pituitary tumors, trauma, or sarcoidosis. Another cause for DI is the failure of response to circulating ADH (nephrogenic). In such cases, the patient has a genetic mutation in the vasopressin receptors, which renders the hormone ineffective.[13]

Dehydration: This results when the loss of water from the body exceeds the intake. It may also be caused by failure to replace obligate water losses. It occurs in several forms. Isotonic dehydration occurs when sodium and water are lost together due to causes such as vomiting, diarrhea, burns, sweating, hyperglycemia, hypoaldosteronism, and intrinsic kidney disease. Hypertonic dehydration occurs when there is a water loss more than sodium loss, which will cause an elevation in serum sodium and osmolality. Excess pure water loss mainly occurs through the lungs, kidneys, and skin. Etiologies are fever, DI, and increased respiration. Hypotonic dehydration is most often caused by diuretics, which cause sodium loss more than water loss. Hypotonic dehydration is characterized by low osmolality and sodium.[14]

Diagnostic Tests

Physical Exam

• Skin turgor: This is assessed by pinching the skin between the forefinger and the thumb and then releasing it. The longer the time taken by the skin to return to its normal contour can indicate dehydration.[15]
• Blood pressure: In dehydration, the total water volume is reduced, and therefore, it may lead to low blood pressure. Also, there may be reflex tachycardia. 
• Mucous membranes examination: Dehydration can manifest as dry mucous membranes. 

Laboratory Tests 

• Arterial blood gas and basic metabolic panel: This is an important test to provide information about the patient's acid-base status and the concentrations of the major ions that mainly contribute to plasma osmolality. 
• Complete blood count with differentials: To measure the blood concentration (hematocrit). It indicates changes to the fluid status inside the vasculature if it is increased or decreased.
• Urinalysis: This can help identify nephrotic syndromes by examining the number of electrolytes and proteins in the urine.
• Water deprivation test: The patient will be deprived of fluid for 8 hours, and his urine will be collected to be analyzed for osmolality and electrolytes, and then there will be an ADH challenge. The effects of subsequent urine collection will also undergo analysis, determining the cause of DI in the patient.[16]

Interfering Factors

Posterior Pituitary and Renal System

During the dehydrated state, the hyperosmolar plasma means less fluid in the plasma, making it more concentrated. With the increase in plasma osmolality, water will move out of the cells, and cells will shrink. There are special neurons in the paraventricular and supraoptic nuclei of the hypothalamus that act as osmoreceptors. When these neurons shrink, they undergo stretch and negative pressure suction; thus, they will be depolarized via transient receptor potential vanilloid cation channels. These channels' function is to increase the charge inside the cells and cause them to depolarize, resulting in signaling inside the posterior pituitary, which will lead to the release of the ADH. The ADH works at the renal principal cells and collecting ducts via the V2 receptors, which will prompt an increase in the cAMP inside the cells. This increase in cAMP will induce aquaporin's insertion in the plasma membrane's apical side, creating a channel through which water can be reabsorbed from the filtrate, leading to a reduction in plasma osmolality.[17]

During the hypoosmolar state, the paraventricular and supraoptic nuclei neurons will not undergo any stretch or negative pressure suction. This state will result in hyperpolarization of the neuron. This will decrease ADH's release from the posterior pituitary gland, allowing the kidneys to excrete more dilute urine and increase the plasma osmolality back to the physiologic set point.

Renin Angiotensin Aldosterone System (RAAS) 

There are special cells in the wall of the distal convoluted tubule of the kidney called macula densa cells; their primary function is to sense sodium chloride's (NaCl) concentration in the filtrate. Two physiologic scenarios can happen: 

1. The filtrate has a low NaCl concentration: The macula densa cells sense this, so they will signal for the dilation of the afferent renal arterioles, which increases the glomerular hydrostatic pressure and helps the return of the glomerular filtration rate toward normal. The macula densa will also release prostaglandin E2, which will increase the release of renin from the juxtaglomerular cells, the primary storage of renin. The conversion of angiotensinogen, which is made in the liver, to angiotensin 1, is catalyzed by renin in the vasculature. Then, angiotensin 1 will be converted to angiotensin 2 in the lungs by the angiotensin-converting enzyme.

The effects of angiotensin 2 are:

• Stimulate the release of ADH from the posterior pituitary gland.
• Increases the blood pressure by the contraction of vascular myocytes, leading to higher hydrostatic pressure, which increases filtrate production. 
• Increases sympathetic activity.
• Increases the tubular NaCl reabsorption and excretion of potassium and water, which results in increased plasma NaCl concentration, which will lead to increased plasma osmolality. 

2. The filtrate has a high NaCl concentration: In this scenario, the cells of the macula densa decrease their release of prostaglandins, which inhibits the RAAS pathway.[18]

Clinical Significance

Alterations in the serum osmolality will cause many clinical implications. It is essential to think about all differential diagnoses; ultimately, further laboratory testing will be necessary to reach a diagnosis. Clinicians should monitor the patient for seizures, peripheral edema, lung edema, or intracranial pressure changes.

Pathologies include: 

• Diabetes insipidus: A disease characterized by lack of ADH (central) or failure of response to circulating ADH (nephrogenic), resulting in diluted, hypoosmolar urine (less than 300mOsm/liter) and concentrated, hyperosmolar plasma (over 300 mOsm/liter). 
• Congestive heart failure: Is a pathology characterized by the dilation and hypertrophy of the left ventricle of the heart that prevents forward blood flow, resulting in decreased end-organ perfusion and elevation of the hydrostatic oncotic pressure, which leads to pulmonary edema and hepatic congestion. These events will decrease renal perfusion, activate the RAAS system, and change the concentrations of solutes in the blood and urine.[19]
• Dehydration: In an acute setting, this will lead to a hypertonic state. 
• Kwashiorkor: The lack of amino acids in an individual's diet due to severe malnutrition results in the liver's inability to synthesize proteins leading to decreased plasma oncotic pressure.
• Liver cirrhosis: This is the final stage of various hepatic insults that render the liver damaged, and therefore it will be ineffective at completing the essential hepatic functions, which include synthesizing proteins, clearing bilirubin, and metabolizing drugs for excretion.[20]
• Psychogenic polydipsia: Characterized by self-induced water intoxication. 
• Nephrotic syndrome: A disorder in the kidney that results in the loss of proteins in the urine leading to hypoosmolar serum.

Enhancing Healthcare Team Outcomes

The management of patients with abnormal serum osmolality needs an interprofessional approach because of the diverse etiologies and multiple challenges in successfully treating the patients without causing further complications. The aim is to control the primary condition causing the abnormality in the serum osmolality and monitor the fluid status and electrolytes. The clinicians (including NPs and PAs), pharmacists, nursing staff, and laboratory techs must work as an interprofessional team to minimize complications and provide the best care. The prognosis for patients with abnormal serum osmolality depends on the cause.

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