Introduction

Osmolality is a colligative property of solutions that depends on the number of dissolved particles in the solution.[1] The term osmolality expresses concentrations relative to the mass of the solvent, whereas the term osmolarity expresses concentrations per volume of solution. Osmolality is thermodynamically accurate because solution concentrations expressed on a weight basis are temperature-independent, whereas those based on volume vary with temperature.[2] Although the term osmolarity is used in the medical literature, osmolality is usually measured.

Osmolality is routinely measured in clinical laboratories for the differential diagnosis of disorders related to hydrolytic balance regulation, renal function, and small-molecule poisonings.[3] Serum and urine osmolality tests are usually measured and compared to determine the diagnosis of any disease that influences osmolality. Serum osmolality is affected by the concentration of blood chemicals like chloride, sodium, proteins, bicarbonate, and glucose. The blood urea nitrogen (BUN) is important for calculating serum osmolality. Specific therapies and toxins that affect an individual’s fluid balance should also be evaluated with serum osmolality. Several formulas are used for serum osmolality, but the Smithline-Gardner formula is considered the most accurate.[4][5] 

The normal serum osmolality ranges from 275 to 295 mOsm/kg.[6] Water normally flows from low to high osmolality. When water moves between plasma and intracellular compartments, the direction depends on both compartments' osmolalities.[7] For example, if a cell is in a relatively hyperosmolar solution, fluid will move toward the highly concentrated compartment to reach homeostasis. As a result, the cell will shrink.

Pathophysiology

Low Serum Osmolality (Hypoosmolar Serum)

Psychogenic polydipsia

This is a psychiatric condition characterized by self-induced water intoxication. The disease process has 3 phases. First, polyuria and polydipsia are followed by reduced water excretion by the kidneys, resulting in hypoosmolar plasma that leads to hyponatremia. The final phase is water intoxication, presenting with delirium, ataxia, nausea, seizures, and vomiting, which could be fatal.[8]

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, leading to dilutional hypoosmolar plasma and hypertension. The treatment can involve medications that block the vasopressin receptor, such as tolvaptan, therapy with hypertonic saline, removing the inciting medications, or treating the primary cause.[9]

Nephrotic syndrome

A general term describes the disease processes that result in excessive proteinuria (over 3 g/d), accompanied by hypertriglyceridemia, hypoalbuminemia, and a hypercoagulable state. The proteinuria occurs when the podocyte foot processes or the glomerular basement membrane is damaged, decreasing serum osmolality and oncotic pressure.[10]

Liver cirrhosis

The liver produces albumin, secreted from the hepatic cells into the extravascular space and then returned to the blood via the lymphatic system. When liver damage occurs, the body cannot produce albumin, which results in a hypoosmolar serum.[11] 

High Serum Osmolality (Hyperosmolar Serum)

Diabetes insipidus (DI)

This disease presents with extensive urine volume excretion, resulting in hyperosmolar plasma (greater than 300 mOsm/kg) and hypoosmolar urine (less than 300 mOsm/kg). DI can result from a lack of ADH (central) due to damage to the neurons responsible for ADH production secondary to pituitary or 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, rendering the hormone ineffective.[12]

Dehydration

This results when the body's water loss exceeds the intake and 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 develops when water loss exceeds sodium, increasing 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 mainly caused by diuretics, which cause sodium loss greater than water loss. Hypotonic dehydration is characterized by low osmolality and sodium.[13]

Specimen Requirements and Procedure

The preferred specimen for serum osmolality testing is typically a blood sample collected in a plain, red-top tube or serum separator tube (SST). The sample is processed to separate the serum from the blood cells. The serum should be removed from the clotted blood cells as rapidly as possible.[3] Specific protocols and procedures may vary depending on the healthcare facility and the laboratory conducting the test, and it is essential to follow their guidelines.

In gross amounts, hemolysis has not interfered with osmolality measured by freezing-point depression. This is because hemoglobin is not an osmotically active particle and does not contribute to the osmolality of the sample.[14] Volatile substances such as alcohol cause a significant bias in osmolality measured using vapor-pressure depression osmometers. This is because alcohol is a volatile substance that can evaporate and cause a decrease in the vapor pressure of the solution, leading to an underestimation of the osmolality.[15] Avoid alcohol-containing antiseptics when collecting samples for osmolality testing using vapor-pressure depression osmometers.

Diagnostic Tests

The following are indicated diagnostic tests to measure serum osmolality:

Physical Exam

• Skin turgor: This is assessed by pinching the skin between the forefinger and the thumb and then releasing it. The time the skin returns to normal contour can indicate dehydration.[16]
• Blood pressure: In dehydration, the total water volume is reduced, which may lead to low blood pressure and reflex tachycardia. 
• Mucous membranes examination: Dehydration can manifest as dry mucous membranes. 

Laboratory Tests 

• Arterial blood gas and basic metabolic panel: This test provides 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: This measures the blood concentration (hematocrit), indicating changes to the vasculature's fluid status.
• Urinalysis: This can help identify nephrotic syndromes by measuring electrolytes and proteins in the urine.
• Water deprivation test: The patient is deprived of fluid for 8 hours, and urine is collected for osmolality and electrolytes, leading to an ADH challenge. The effects of subsequent urine collection undergo analysis to determine the cause of DI in the patient.[17]

Testing Procedures

The 4 physical properties of a solution that change with variations in the number of dissolved particles in the solvent are osmotic pressure, vapor pressure, boiling point, and freezing point. Osmometers measure osmolality indirectly by measuring one of these colligative properties, which change proportionally with the osmotic pressure. Due to its simplicity and the fact that vapor pressure osmometers cannot detect volatile compounds like methanol, most clinical laboratories employ the freezing point depression method to evaluate osmolality. Furthermore, freezing point depression, unlike vapor pressure, is independent of changes in ambient temperature.[18]

The freezing point depression osmometer has several critical components that work together seamlessly to ensure precise results. At the heart of the osmometer is a thermostatically controlled freezing chamber regulated by a Peltier device. The Peltier device cools the sample where the freezing point depression is measured. During this process, the solution is supercooled below 0 °C. To initiate the freezing process of the sample, the osmometer is equipped with a mechanism designed to agitate the sample tube. This action, often called "seeding," ensures that the freezing process begins uniformly. A thermistor probe monitors the sample's temperature during this process. A thermistor is a type of resistor whose resistance undergoes rapid and predictable changes in response to temperature variations. This probe is connected to a circuit that processes the signal from the thermistor, measuring the sample's temperature.[1]

A galvanometer plays a vital role in displaying the freezing curve. This curve is a graphical representation of how the temperature of the sample evolves as it undergoes the freezing process. The galvanometer is a visual guide to interpreting the freezing curve.[18] Additionally, the osmometer is equipped with a measuring potentiometer. This component works with the galvanometer, providing further precision in the measurement process. A potentiometer is a type of variable resistor that can be adjusted to measure voltage or current, and in this context, it aids in fine-tuning the measurements.[19] The vapor-pressure osmometer measures the dew-point depression of the vapor, that is, the vapor in equilibrium with the solution being measured. The more dissolved particles present (increased osmolality), the lower the vapor pressure of the aqueous component of the solution.[20]

Interfering Factors

Posterior Pituitary and Renal System

During states of dehydration, hyperosmolar plasma indicates an increased solute-to-water ratio. The hyperosmolality leads to water leaving cells and cells shrinking. Some neurons in the paraventricular and supraoptic nuclei of the hypothalamus sense these changes in osmolality called osmoreceptors. These neurons undergo stretch and negative pressure suction, leading to depolarization via vanilloid cation channels. The depolarization leads to signaling inside the posterior pituitary and ADH release. The ADH works at the renal principal cells and increases the second messenger cAMP. This increase in cAMP induces aquaporins in the plasma membrane's apical side, and water is reabsorbed, reducing osmolality.[21] During the hypoosmolar state, the paraventricular and supraoptic nuclei neurons do not undergo stretch or negative pressure suction. This results in neuron hyperpolarization, decreasing ADH release from the posterior pituitary gland, and returns plasma osmolality to the physiological set point.

Renin Angiotensin Aldosterone System (RAAS) 

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

1. The filtrate has a low NaCl concentration: The macula densa cells sense this, so they signal for the dilation of the afferent renal arterioles, which increases the glomerular hydrostatic pressure and returns the glomerular filtration rate toward normal. The macula densa cells also release prostaglandin E2, increasing renin release from the juxtaglomerular cells. The conversion of angiotensinogen in the liver to angiotensin-1 is catalyzed by renin in the vasculature. Then, angiotensin-1 is 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.
• Increase the blood pressure by the contraction of vascular myocytes, leading to higher hydrostatic pressure, and increases filtrate production. 
• Increase sympathetic activity.
• Increase the tubular NaCl reabsorption and excretion of potassium and water, increasing plasma NaCl concentration and increasing plasma osmolality. 

2. The filtrate has a high NaCl concentration: The cells of the macula densa decrease the release of prostaglandins, inhibiting the RAAS pathway.[22]

Results, Reporting, and Critical Findings

The reference interval for plasma osmolality varies, but a common reference interval is 275 to 295 mOsmol/kg.[2] A comparison of measured and calculated osmolality can reveal an osmolar gap, indicating exogenous osmotic substances, commonly alcohol.[23] Comparison of calculated and measured osmolalities can also confirm or rule out suspected pseudo hyponatremia caused by the electrolyte exclusion effect.[24]

Clinical Significance

Changes in the serum osmolality cause many clinical scenarios. Ultimately, further laboratory testing is 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 central ADH or failure of response to circulating nephrogenic ADH, resulting in diluted, hypoosmolar urine (less than 300 mOsm/kg) and concentrated, hyperosmolar plasma (over 300 mOsm/kg). 
• Congestive heart failure: 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 decrease renal perfusion, activate the RAAS system, and change the concentrations of solutes in the blood and urine.[25]
• Dehydration: This leads to a hypertonic state in an acute setting. 
• 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 the essential hepatic functions diminish, which include synthesizing proteins, clearing bilirubin, and metabolizing drugs for excretion.[26]
• 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.

Quality Control and Lab Safety

Quality control is essential to laboratory testing to ensure accurate and reliable results.[27] The Clinical Laboratory Improvement Amendments (CLIA) of 1988 established quality control requirements for laboratory testing, including proficiency testing, quality control and assessment, and personnel requirements. The osmometer should be run daily or after each batch of samples to ensure quality control. For non-waived tests, laboratory regulations require, at the minimum, analysis of at least 2 levels of quality control materials every 24 hours.[28] If necessary, laboratories can assay QC samples more frequently to ensure accurate results. Assaying QC samples after an analyzer has been calibrated or maintained to confirm the method's accurate performance is important.[29]

The quality control should be in a matrix that closely resembles the tested specimen to provide the best control for osmolality testing. The more similar a control is to the patient sample, the greater confidence an operator has in the instrument's performance. The quality controls should have tight ranges to spot shifts in instrument performance. [30] The acceptable range and guidelines for interpreting QC outcomes rely on the likelihood of identifying a noteworthy analytical error and keeping the false alert rate at an acceptable level. Before choosing the appropriate QC rules, defining the preferred performance characteristics for each measurement is crucial.[31] Typically, Westgard multi-rules are employed to assess the quality control runs. In a declared out-of-control run, a thorough system investigation is conducted to pinpoint the underlying issue. No analysis should be conducted until the problem has been rectified.[32]

The laboratory must participate in the external quality control or proficiency testing program. The proficiency testing plan should be integrated into the lab's quality assurance (QA) and overall quality program.[33] Clinical lab safety is an essential cornerstone of healthcare practice, ensuring the protection of both healthcare professionals and patients. It encompasses a range of protocols and precautions designed to handle biological materials and hazardous substances with utmost care.[34] This includes the proper use of personal protective equipment (PPE) like gloves, lab coats, and safety goggles, as well as the meticulous handling of specimens to prevent contamination and maintain accuracy in diagnostic testing. Rigorous decontamination routines and proper waste disposal practices are also crucial to prevent the spread of infections. Training and education programs also equip lab personnel with the knowledge and skills to respond effectively to emergencies and incidents.[35] By upholding these practices, clinical laboratories play a pivotal role in delivering accurate, reliable, and safe diagnostic services, contributing significantly to the quality of patient care.

Enhancing Healthcare Team Outcomes

Managing patients with abnormal serum osmolality demands an interprofessional approach to avoid further complications. The primary goal is to control the underlying condition responsible for the abnormality in serum osmolality and closely monitor the fluid status and electrolyte balance. To ensure the best possible care and minimize complications, clinicians, pharmacists, nursing staff, and laboratory technicians must work together as an interprofessional team. The prognosis for patients with abnormal serum osmolality depends on the underlying cause.

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Disclosure: Omer Najem declares no relevant financial relationships with ineligible companies.

Disclosure: Maulik Shah declares no relevant financial relationships with ineligible companies.

Disclosure: Muhammad Zubair declares no relevant financial relationships with ineligible companies.

Disclosure: Orlando De Jesus declares no relevant financial relationships with ineligible companies.