Hyponatremia: reasoning by osmolality and volume

A 79-year-old woman is admitted after a fall at home, with a femoral neck fracture. Admission tests show sodium of 126 mmol/L. She takes a thiazide diuretic for high blood pressure and an antidepressant for a few months. Her daughter reports that her mother has been "slower" and unsteady over the past few weeks, and that she ate little because she lost her appetite.

Hyponatremia is the most common electrolyte disorder in clinical practice, and also one of the most poorly investigated. The low number on the test draws attention, but the cause usually goes unnamed in the chart. Without a cause, there is no plan, and the patient is discharged with the same low sodium they came in with.

The diagnostic reasoning for hyponatremia is one of the best examples of a well-built algorithm in internal medicine. It rests on three questions in sequence: is the hyponatremia truly hypotonic, is the kidney diluting the urine, and what is the patient's volume status. This text walks through that path step by step, without going into correction or treatment.

Key points

• The first question is whether the hyponatremia is hypotonic, and plasma osmolality answers it.
• Urine osmolality shows whether the kidney is able to dilute the urine.
• Urine sodium and the volume assessment separate the main causes.
• The syndrome of inappropriate antidiuretic hormone secretion is a diagnosis of exclusion, with its own criteria.
• In older adults, the cause is usually multifactorial, and medications appear frequently.

Why hyponatremia deserves careful reasoning

Hyponatremia is defined by low serum sodium. A review on the syndrome of inappropriate antidiuretic hormone secretion uses the threshold of less than 135 mEq/L and notes that this is the most common electrolyte disorder in clinical practice (Mentrasti et al., 2020). The exact thresholds vary slightly between sources, but the concept is the same.

Low sodium is not an innocent finding. A meta-analysis gathered 81 studies with 850,222 patients, of whom 17.4 in 100 had hyponatremia, and showed a relative risk of death of 2.60 in those with low sodium (Corona et al., 2013). The authors concluded that even a moderate reduction in sodium is associated with a higher risk of death in several common clinical conditions.

Chronic does not mean benign

Mild, chronic hyponatremia is often tolerated as if it had no consequence. A review on hyponatremia and the brain shows that the chronic form is associated with subtle neurological changes, such as attention deficit, falls and gait imbalance, with fall risk especially marked in older adults (Gankam Kengne and Decaux, 2018).

Another review draws attention to the same point: chronic hyponatremia causes gait disturbances and attention deficits, but physicians often tolerate it as if it were benign (Hoorn et al., 2009). The patient in the case, who fell and fractured her femur, illustrates this link well.

The problem: poorly investigated hyponatremia

The weak point in hyponatremia management is usually in the diagnosis, not the treatment. The review by Hoorn et al. states that recent studies show insufficient diagnostic testing and inadequate management (Hoorn et al., 2009).

What the charts show

A British multicenter study reviewed the charts of the first 100 patients admitted with sodium of 128 mmol/L or less at three hospitals (Tzoulis et al., 2014). Only 23 of the 100 patients had paired osmolality and sodium in blood and urine, and 31 in 100 had an assessment of adrenal reserve. The cause of hyponatremia was not recorded in 58 in 100 episodes.

The same study showed in-hospital mortality of 16 in 100 and a mean stay of 17.5 days, and 53 of the 84 patients who were discharged still had low sodium (Tzoulis et al., 2014). Without the initial tests, the reasoning has nowhere to start.

This data aligns with the lessons from morbidity and mortality sessions: often, the error is not one of knowledge but of process, such as failing to order the right test at the right time.

Guidelines agree on the path

A systematic review found ten guidance documents on hyponatremia, five guidelines and five consensus statements, of variable quality (Nagler et al., 2014). Seven of them included diagnostic recommendations, and all used the same logic: serum osmolality to confirm hypotonic hyponatremia, then volume status, urine sodium and urine osmolality to classify.

The documents differed, however, in cutoffs, additional tests and when to start the investigation (Nagler et al., 2014). The path is the same, but the numbers can change from one guideline to another, and it is necessary to know which one is being used.

Step 1: is the hyponatremia hypotonic?

Sodium is the main determinant of plasma osmolality, but not the only one. Before looking for the cause, it is necessary to confirm that water is truly in excess relative to solute.

Hyponatremia with normal or high osmolality

The British algorithm by Grant et al. advises checking plasma osmolality and considering causes of hypertonic hyponatremia, such as hyperglycemia or mannitol infusion, when it is above 275 mOsm/kg (Grant et al., 2015). In these cases, an osmotically active substance pulls water from cells into plasma and dilutes sodium.

A review on critically ill patients recalls that hyperglycemia is the most frequent situation of this dilutional hyponatremia and that sodium falls by about 2.4 mEq/L for each 100 mg/dL increase in glucose (Overgaard-Steensen et al., 2013). The same review mentions pseudohyponatremia, an uncommon measurement error in patients with hyperlipidemia or hyperproteinemia.

Why this step comes first

Skipping the first step leads to serious errors. The decompensated diabetic patient with low sodium does not have excess water to treat, but high glucose to explain it. The reasoning of pretest probability helps here: in someone with hyperglycemia, the hypothesis of dilutional hyponatremia rises well before any other test.

Step 2: is the kidney diluting the urine?

Once hypotonic hyponatremia is confirmed, the next question is about the kidney. Faced with diluted plasma, a normal kidney should produce very dilute urine to eliminate the excess water.

Low urine osmolality

In the British algorithm, urine osmolality below 100 mOsm/kg points to primary polydipsia or to so-called beer drinker's potomania, a diet poor in solute that reduces the capacity to eliminate free water (Grant et al., 2015). In these situations, the kidney does what it should, but water intake exceeds the capacity for excretion.

The review by Mentrasti et al. describes the same reasoning: urine below 100 mOsm/kg indicates maximum dilution, usually due to excessive intake of water or beer with low solute intake (Mentrasti et al., 2020). A diet poor in protein, common in older adults who eat little, falls into this group and recalls the "tea and toast" syndrome described in the review by Filippatos et al. on older adults (Filippatos et al., 2017).

Urine osmolality above 100

When urine osmolality is above 100 mOsm/kg, the kidney is not diluting urine as it should, and antidiuretic hormone is usually active. The review by Mentrasti et al. recalls that, in this scenario, hypothyroidism, glucocorticoid deficiency and, especially, the syndrome of inappropriate antidiuretic hormone secretion must be considered (Mentrasti et al., 2020).

Step 3: volume and urine sodium

From here on, the reasoning splits according to the patient's extracellular volume and urine sodium. It is the most difficult step, because clinical assessment of volume is imprecise.

The three classic groups

The traditional classification separates the hypovolemic, euvolemic and hypervolemic patient. In the British algorithm, the hypervolemic patient has signs such as edema, raised jugular venous pressure, left ventricular failure or ascites, and the focus is the underlying disease, such as heart failure or cirrhosis (Grant et al., 2015).

In the euvolemic patient with plasma osmolality below 275 mOsm/kg and urine osmolality above 100 mOsm/kg, the algorithm directs measuring the urine sodium (Grant et al., 2015). The syndrome of inappropriate secretion is the likely diagnosis if the urine sodium is greater than 20 mmol/L, and a value lower than 20 mmol/L should lead to reassessing the volume, because it usually reflects depletion of intravascular volume.

Step	Question	Finding	Main hypotheses
1	Is the hyponatremia hypotonic?	Plasma osmolality above 275 mOsm/kg	Hyperglycemia, mannitol
2	Does the kidney dilute the urine?	Urine osmolality below 100 mOsm/kg	Primary polydipsia, low-solute diet
3	How is the volume?	Edema, ascites, raised jugular	Heart failure, cirrhosis
3	What is the urine sodium in the euvolemic patient?	Urine sodium above 20 mmol/L	Inappropriate secretion of antidiuretic hormone, after excluding other causes
3	What is the urine sodium in the euvolemic patient?	Urine sodium below 20 mmol/L	Reassess volume, intravascular depletion

Table source: Grant et al., 2015.

Volume misleads

Volume assessment is the weakest link in the algorithm. A review on the critically ill patient states that the traditional classifications by volume are notoriously difficult to use in practice and that several combined mechanisms are common (Overgaard-Steensen et al., 2013). The same patient can have volume loss and excess antidiuretic hormone at the same time.

The study with older adults admitted for fracture showed this in practice: 73 out of every 100 episodes of hyponatremia had a multifactorial cause (Cumming et al., 2014). Recognizing this overlap is part of reasoning in the face of diagnostic uncertainty.

The syndrome of inappropriate antidiuretic hormone secretion

The syndrome of inappropriate antidiuretic hormone secretion, known by the acronym SIADH, is the most remembered cause of euvolemic hyponatremia. A review on inflammation and hyponatremia describes it as the most common cause of euvolemic hyponatremia (Park et al., 2013).

A diagnosis of exclusion

The review by Mentrasti et al. recalls that SIADH remains a diagnosis of exclusion, with criteria originally described by Bartter and Schwartz (Mentrasti et al., 2020). The essential criteria include effective serum osmolality below 275 mOsm/kg, urine osmolality above 100 mOsm/kg, clinical euvolemia, urine sodium above 30 mmol/L with normal salt and water intake, normal adrenal, thyroid, pituitary and renal function and no recent use of diuretics.

Among the auxiliary criteria, the same review lists serum uric acid below 4 mg/dL, serum urea below 21.6 mg/dL and failure to correct the hyponatremia with saline (Mentrasti et al., 2020). Note that the urine sodium cutoff is 30 mmol/L in this review and 20 mmol/L in the British algorithm, an example of the divergence between documents pointed out by Nagler et al.

Do not forget adrenal and thyroid

Excluding glucocorticoid deficiency and hypothyroidism is mandatory before closing the diagnosis of SIADH. The review on older adults insists on this point and states that special attention is needed to exclude endocrinopathies before diagnosing SIADH in this population (Filippatos et al., 2017). In the British study, only 31 out of every 100 patients had their adrenal reserve assessed (Tzoulis et al., 2014).

Look for the cause of SIADH

SIADH is not the end of the reasoning, it is the beginning of another. It can originate in tumors, lung diseases, diseases of the nervous system, pain, nausea, medications and inflammation. The review by Park et al. shows that inflammatory cytokines, such as interleukin 6 and interleukin 1 beta, participate in the release of antidiuretic hormone and in hyponatremia in inflammatory diseases (Park et al., 2013).

An imitator: cerebral salt wasting

In patients with diseases of the central nervous system, one differential diagnosis deserves special attention. The review by Mentrasti and colleagues describes cerebral salt wasting as a cause of hyponatremia reported especially after aneurysmal subarachnoid hemorrhage, but also after head trauma, infections, brain tumors and pituitary surgery (Mentrasti and colleagues, 2020).

The mechanism is still unclear, and the authors note that distinguishing this condition from SIADH is important and difficult, because the management is opposite. For reasoning, the central clue is volume: in cerebral salt wasting, the patient loses sodium and volume through urine, while in SIADH volume is preserved. Once again, volume assessment, with all its limitations, decides the direction.

Inflammation as a trigger

The review by Park and colleagues lists several inflammatory diseases associated with hyponatremia, such as pneumonia, tuberculosis, meningitis, encephalitis, HIV infection and malaria (Park and colleagues, 2013). The authors describe that serum sodium correlates inversely with the percentage of neutrophils and with C-reactive protein, and that interleukins 6 and 1 beta are higher in patients with hyponatremia.

In practice, this means that hyponatremia in a patient with pneumonia is not an isolated finding: it is part of the inflammatory picture and should enter the reasoning about the severity and course of the underlying disease.

Medications: the cause on the prescription

The medication list is a mandatory part of the investigation. A review on drug-induced hyponatremia points to psychotropics, chemotherapy agents and thiazide diuretics as the main causes in current practice (Kim, 2022).

Different mechanisms, same result

The same review explains that some drugs increase the release of antidiuretic hormone, while others, such as antipsychotics, antidepressants, anticonvulsants and thiazides, appear to act through mechanisms within the kidney, with the hormone suppressed (Kim, 2022). For diagnostic reasoning, the effect is similar: urine inappropriately concentrated in a patient with no other explanation.

The particular case of older adults

The review by Filippatos and colleagues states that, in older adults, hyponatremia is caused mainly by medications, especially thiazides and antidepressants, by SIADH or by endocrinopathies, and that the cause is multifactorial in a significant proportion of patients (Filippatos and colleagues, 2017).

A Scottish prospective study of older adults admitted for fragility fracture illustrates this scenario. Of 212 eligible patients, 127 were included, and the prevalence of hyponatremia on admission was 13.4 per 100, with another 12.6 per 100 developing hyponatremia during the hospital stay (Cumming and colleagues, 2014). The hypovolemic form predominated, in 70 per 100 episodes.

The most common possibly causal factors were thiazide diuretics, in 76 per 100 episodes, dehydration, in 70 per 100, proton pump inhibitors, in 70 per 100, SIADH, in 27 per 100, and mirtazapine, in 15 per 100 (Cumming and colleagues, 2014). The authors concluded that SIADH was not the most common cause in this group, contrary to what is usually assumed.

This result is a good antidote against availability bias and other shortcuts: the cause that comes to mind first is not always the most likely in the population being treated.

Building the reasoning step by step

The hyponatremia algorithm can be summarized in a sequence that fits on a pocket card.

1. Confirm hyponatremia and check glucose: is plasma osmolality low?
2. If plasma osmolality is not low, consider hyperglycemia, mannitol or measurement error.
3. Measure urine osmolality: below 100 mOsm/kg suggests excessive water intake or low solute intake.
4. Assess volume clinically, knowing that this assessment is imprecise.
5. Measure urine sodium and interpret it in light of volume and diuretic use.
6. In the euvolemic patient, rule out hypothyroidism and glucocorticoid deficiency before diagnosing SIADH.
7. Review all medications and look for the underlying cause of SIADH.

The tests that need to be collected together

The reasoning depends on tests collected at the same time: sodium, glucose and osmolality in the blood, osmolality and sodium in the urine. The British study showed that only 23 of the 100 patients had these paired measurements (Tzoulis and colleagues, 2014). Recording the results and the hypothesis in the medical record keeps the investigation from starting over from scratch on every shift.

Back to the patient in the case

The 79-year-old patient has a sodium of 126 mmol/L, takes a thiazide and an antidepressant, eats little and has fallen. The first step is to confirm that the hyponatremia is hypotonic, with glucose and plasma osmolality. Then, urine osmolality shows whether the kidney is diluting the urine, and urine sodium, interpreted with care because she takes a diuretic, helps separate volume loss from SIADH.

In practice, the cause is likely multifactorial, as in the study with older adults with fractures, in which thiazides and dehydration were the most common factors (Cumming and colleagues, 2014). Low solute intake may also contribute. Before labeling SIADH, thyroid function and adrenal reserve must be assessed (Filippatos and colleagues, 2017).

How NEXO helps train this reasoning

In NEXO, the case of the day is fictional, with a real clinical presentation and up to six progressive clues, and you propose the diagnosis by searching for the ICD-10 code.

The limits of using the game are described on the NEXO Economy page. If you research the teaching of clinical reasoning, the page for Researchers explains how to get in touch. Professionals who write or review cases find information on Curator and on Creators, and institutions can learn about the proposal on the partnerships page. Training clinical decision-making and searching for the right ICD-10 code complete this practice.

Frequently asked questions

Why measure plasma osmolality if the sodium is already low?

Because not every hyponatremia is hypotonic. In hyperglycemia, for example, sodium falls because water enters the cells from the plasma, and osmolality is not low (Overgaard-Steensen and colleagues, 2013). The algorithm starts with this question so as not to treat as excess water what is excess glucose (Grant and colleagues, 2015).

Does urine sodium work in people who take a diuretic?

It works poorly. The diuretic raises urine sodium even when the patient has low volume, and the absence of recent diuretic use is one of the essential criteria for diagnosing SIADH (Mentrasti and colleagues, 2020). In these patients, the result must be interpreted with the context.

Is SIADH the most common cause of hyponatremia?

It depends on the population. It is the most common cause of euvolemic hyponatremia (Park and colleagues, 2013), but in older adults hospitalized for fractures SIADH came behind thiazides, dehydration and proton pump inhibitors (Cumming and colleagues, 2014).

Does mild hyponatremia need to be investigated?

It does. Even moderate hyponatremia is associated with a higher risk of death (Corona and colleagues, 2013), and the chronic form is linked to falls and gait changes (Gankam Kengne and Decaux, 2018). Investigating the cause is the first step in deciding what to do.

What is the role of clinical volume assessment?

It is necessary, but imprecise. A review on the critically ill patient states that volume classifications are hard to apply in practice and that several mechanisms often coexist (Overgaard-Steensen and colleagues, 2013). Therefore, volume must be interpreted together with the blood and urine tests.

Take-home messages

• Hyponatremia is common, is associated with higher mortality and is often poorly investigated.
• Plasma osmolality confirms whether the hyponatremia is hypotonic.
• Urine osmolality shows whether the kidney is diluting the urine.
• Volume and urine sodium separate the causes, but volume assessment is imprecise.
• SIADH is a diagnosis of exclusion, which requires ruling out hypothyroidism and glucocorticoid deficiency.
• In older adults, medications and multiple causes are the rule, not the exception.

References

1. Corona G, Giuliani C, Parenti G, et al. Moderate hyponatremia is associated with increased risk of mortality: evidence from a meta-analysis. PLoS One. 2013. PMID 24367479.
2. Cumming K, Hoyle GE, Hutchison JD, et al. Prevalence, incidence and etiology of hyponatremia in elderly patients with fragility fractures. PLoS One. 2014. PMID 24505459.
3. Filippatos TD, Makri A, Elisaf MS, et al. Hyponatremia in the elderly: challenges and solutions. Clin Interv Aging. 2017. PMID 29180859.
4. Gankam Kengne F, Decaux G. Hyponatremia and the Brain. Kidney Int Rep. 2018. PMID 29340311.
5. Grant P, Ayuk J, Bouloux PM, et al. The diagnosis and management of inpatient hyponatraemia and SIADH. Eur J Clin Invest. 2015. PMID 25995119.
6. Hoorn EJ, van der Lubbe N, Zietse R. SIADH and hyponatraemia: why does it matter? NDT Plus. 2009. PMID 19881934.
7. Kim GH. Pathophysiology of Drug-Induced Hyponatremia. J Clin Med. 2022. PMID 36233678.
8. Mentrasti G, Scortichini L, Torniai M, et al. Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH): Optimal Management. Ther Clin Risk Manag. 2020. PMID 32801723.
9. Nagler EV, Vanmassenhove J, van der Veer SN, et al. Diagnosis and treatment of hyponatremia: a systematic review of clinical practice guidelines and consensus statements. BMC Med. 2014. PMID 25539784.
10. Overgaard-Steensen C, Ring T. Clinical review: practical approach to hyponatraemia and hypernatraemia in critically ill patients. Crit Care. 2013. PMID 23672688.
11. Park SJ, Shin JI. Inflammation and hyponatremia: an underrecognized condition? Korean J Pediatr. 2013. PMID 24416046.
12. Tzoulis P, Evans R, Falinska A, et al. Multicentre study of investigation and management of inpatient hyponatraemia in the UK. Postgrad Med J. 2014. PMID 25398584.