DOI: 10.

15386/cjmed-619 Reviews

DIFFICULTIES IN THE DIAGNOSIS AND MANAGEMENT OF

HYPONATREMIA

MIHAELA MOCAN, LIA MANUELA TERHEŞ, SORIN NICU BLAGA

Department of Internal Medicine, 1st Medical Clinic, Iuliu Hatieganu University

of Medicine and Pharmacy, Cluj-Napoca, Romania

Abstract

Hyponatremia is the most common electrolyte imbalance encountered in

clinical practice. Beside the difficulty of the etiological diagnosis, the general lack
of awareness regarding the negative impact of hyponatremia on the quality of life
and the lack of targeted treatments until recent years may be responsible for the poor
management of the disorder.
Therefore we consider of utmost importance to improve the knowledge regarding
the diagnosis and management of hyponatremia, by underlining the difficulties of the
etiological diagnosis and its management.
In this respect, a short and updated literature review, with a critical appraisal
of the latest guidelines will provide detailed information on how to systematically
evaluate and treat the hyponatremic patients.

Keywords: hyponatremia, inappropriate ADH syndrome, vasopressin

antagonists, water-electrolyte imbalance

Introduction the diversity of underlying disease states associated with

Hyponatremia (serum Na levels of <135 mEq/l), the condition and, until the last few years, a lack of targeted
is the most common electrolyte imbalance encountered in treatments.
clinical practice, affecting up to 15–28% of hospitalized Thus, we consider of utmost importance to improve
patients [1]. Its incidence varies between hospitals and the knowledge regarding the diagnosis and management of
departments, with a frequency of 36% in internal medicine hyponatremia. In this respect, a short and updated literature
department, very similar to that found in surgical or intensive review will provide detailed information on the diagnosis
care departments, as showed by Hoorn et al. [2]. Both and management of hyponatremic patients.
moderate and especially severe hyponatremia (Na<125
mEq/l) found in newly admitted hospital patients is linked Clinical presentation
with a significantly elevated in-hospital mortality of 28% Neurological symptoms of hyponatremia (gait
compared to 9% in-hospital mortality in normonatremic, disturbances, cognitive dysfunction and dizziness) may
matched controls [3]. Mortality in fact increases when lead to falls and subsequent injuries requiring medical
serum Na levels are below 135 mEq/l. Patients with care. The symptoms are subtle, difficult to diagnose
hyponatremia also have varied clinical presentations that and rarely identified as determined by hyponatremia,
include differing symptomatology, underlying etiology and especially in older patients. Even though cognitive and/
fluid volume status. or geriatric functional tests regularly reveal a significant
Despite frequently observed in hospitalized impairment in patients with hyponatremia as compared to
patients, the diagnosis and management of hyponatremia normonatremic ones, hyponatremia is often overseen or
is neither easy nor optimal [4]. This may be attributable to not given full attention [3]. Furthermore, if hyponatremia
is diagnosed, it is regularly classified to be asymptomatic
Manuscript received: 10.12.2015 and the underlying reasons often remain obscure [4]. Thus,
Accepted: 07.01.2016
Address for correspondence: mihaela.mocan@gmail.com the etiology of hyponatremia needs to be systematically
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determined in order to apply rapid and correct therapeutic patients sometimes die of brain herniation.
sanctions. In chronic hyponatremia, brain cells extrude
Two factors influence the severity of the clinical organic solutes from their cytoplasm, allowing intracellular
picture: osmolality to equal plasma osmolality without a large
• biochemical severity based on concentration of increase in cell water. Therefore, patients with chronic
sodium in serum: (>48 hours) hyponatremia have more modest symptoms
- mild: 130–135 mEq/l and almost never die of brain herniation. Symptoms like
- moderate: 125–129 mEq/l headache, modest nausea in general reflect a more moderate
- severe: < 125 mEq/l severity associated with insidious onset [5].
• speed of development Thus, a brief anamnesis (regarding the medical
- acute (usually <48h) history, physical activity, drugs) and physical examination
- chronic [5]. (hydration status, cardiovascular status, neurological exam)
Clearly, the symptoms of hyponatremia depend on the should be performed (Table I) in a patients with acute
time lapsed since the start of hyponatremia. Hyponatremia hyponatremia. Usually, the clinical picture is correlated
with rapid onset (<48 h) is associated with severe symptoms with hyponatremia only after the biological confirmation
caused by cerebral edema and high intracranial pressure: of low Na levels and the exclusions of other organic
epileptic convulsions, pronounced somnolence or coma, neurologic diseases.
vomiting and compromised respiratory regulation. These

Table I. Anamnesis and physical examination in hyponatremic patients.

Anamnesis
Medical history: malignancy, surgical intervention
Life and work conditions: excessive physical effort, extended sauna visit, polydipsia, potomania (beer)
Initiation of new drugs or increasing dosage of older ones: diuretics – especially thiazides,
antidepressants, antibiotics, analgesics etc.
Physical examination
Signs of dehydration or volume overload
Neurological examination
Cardiovascular status (heart rate, blood pressure)

Etiological diagnosis algorithm of hyponatremia, and the establishment of efficacy and safety
hyponatremia of vasopressin receptor antagonist therapy in more severe
Experts from different specialties often propose cases.
different diagnostic algorithms to facilitate the management Most of the recommendations in relation to
of hyponatremic patients in the hospital settings. diagnosis, investigation and management in the emergency
Traditionally, the diagnosis and treatment of hyponatremia setting are convergent. There is variation in relation to the
have fallen within the remit of practitioners of nephrology use of interventions after fluid restriction. Where there is
and endocrinology. Therefore, to obtain a common and a significant divergence, this is acknowledged in the text.
holistic view, the European Society of Intensive Care Using this guidelines and the facts known from
Medicine, the European Society of Endocrinology and previous studies, especially those extracted from critical
the European Renal Association – European Dialysis and care experience, where patients with severe hyponatremia
Transplant Association, represented by European Renal are evaluated and treated, a diagnosis algorithm has been
Best Practice, have developed the European Clinical designed (Figure 1). This algorithm is useful both in
Practice Guideline (2014) on the diagnostic approach and acute and chronic conditions. It divides hyponatremia in
treatment of hyponatremia [6]. three categories according to the plasmatic osmolality.
For the USA, guidelines on hyponatremia have been Hypertonic hyponatremia (also pseudohyponatremia) and
issued by an expert panel around Verbalis et al. in 2007, normotonic hyponatremia are two conditions that should be
updated in 2013 [7]. The expert panel stressed as notable ruled out before managing hyponatremia.
developments the importance of treating mild to moderate

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Figure 1. Etiological diagnosis algorithm of hyponatremia. Adapted from Schrier et al. [8]
and Katzel et al. [9]. SIADH: Syndrome of Inappropriate Antidiuretic Hormone Secretion.

Pseudohyponatremia is due to marked elevation of disease. These conditions are not difficult to identify if they
lipids or proteins in plasma causing artifactual decrease in are systematically searched [6].
serum sodium concentration as a larger relative proportion Euvolemic hyponatremia is the most problematic
of plasma is occupied by excess lipid or proteins. from the etiological point of view. If the urinary Na
Hyponatremia with normal osmolality appears from osmotic excretion is below 20 mEq/l, water intoxication or
shift of water from intracellular fluid to extracellular fluid psychiatric disorders such as psychogenic polydipsia or
due to additional solutes in plasma, e.g. glucose, mannitol, potomania may be suspected. If the urinary Na excretion
and radiographic contrast agents [8]. is over 20 mEq/l and hypothyroidism, glucocorticoid
Once these two conditions are ruled out, the deficiency or thiazides were excluded, then the Syndrome
diagnosis of hypotonic hyponatremia depends on of Inappropriate Antidiuretic Hormone Secretion (SIADH)
volemic status that could be appreciated clinically or by may be the cause of hyponatremia. Clearly, this is an
central venous pressure determination. In hypovolemic exclusion diagnosis with its own specific pathophysiologic
hyponatremia, there is a deficit of both total body water mechanism, etiology and treatment.
and sodium, but relatively less deficit of water. A history
of digestive losses (vomiting, diarrhea), or renal losses Definitions, etiology, pathophysiologic
(diuretic use, or hyperglycemia with glucosuria) along with mechanisms, and diagnosis criteria of SIADH
increased clinical signs of dehydration (thirst, weight loss, SIADH was first described by Schwartz and
orthostatic hypotension and tachycardia, and dry mucous colleagues in 2 patients with bronchogenic lung carcinoma
membranes) are arguments for hypovolemic hyponatremia. as early as 1957 [10].
If the fluid and sodium losses are extra-renal, such SIADH is a disease categorized as hypotonic
as gastrointestinal losses, urinary Na should be less 10 hyponatremia; it is considered euvolemic, even though a
mEq/l. On the contrary, if the loses of water and Na are small amount of volume expansion is caused by excess of
of renal causes than urinary Na should be over 20 mEq/l. renal water reabsorption through inappropriate antidiuretic
Hypervolemic hyponatremia is related to systemic diseases hormone (ADH) secretion.
causing water retention: congestive heart failure, nephrotic General anesthesia, nausea, pain, stress and a variety
syndrome, cirrhosis or renal failure (acute or chronic). of drugs are non-specific but potent stimuli for the secretion
In this case the treatment is addressed to the underlying of vasopressin and a frequent cause of SIADH in hospitalized

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patients. The most frequent causes of SIADH include cancers from effective serum osmolality or circulating volume.
(e.g. small cell carcinoma of the lung) and diseases of the It may result from increased pituitary secretion or from
lung (e.g. pneumonia) or central nervous system (CNS) (e.g. ectopic production. The excessive ADH secretion causes
subarachnoid hemorrhage) (Figure 2) [6,11]. water retention by increasing water permeability in the renal
Recently, several genetic disorders causing SIADH collecting duct. Consequently, the increased glomerular
have been identified. The first is the polymorphisms in the filtration rate (GFR) due to the volume expansion and
genes encoding the hypothalamic osmoreceptor, transient vasodilating effect of increased circulating atrial/brain
receptor potential vanilloid type 4 (TRPV4), a gene that natriuretic peptides can increase sodium excretion, but
encodes for an osmosensitive calcium channel expressed there is also decreased tubular transport of sodium due to
in osmosensing neurons [12]. The second is a gain-of- unknown mechanism [11].
function mutation in the vasopressin 2 receptor, resulting in “The clinical description of the syndrome changed
a constitutively activated receptor causing increased water little since its original observation” [14] and the guidelines
re-absorption and chronic hyponatremia [13]. adopted a set of criteria for the diagnosis that are detailed
The inappropriate secretion occurs independently in Table II.

Figure 2. Causes of SIADH. Adapted from 2014 European Guideline [6] with modifications from Grant et al. [11]. CNS:
central nervous system; SSRI: serotonin-specific reuptake inhibitors; MAOI: Monoamine oxidase inhibitors; PPIs: proton
pomp inhibitors.

Table II. SIADH diagnosis criteria according to 2014 European Guideline [6].

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Management of hyponatremia correction of hyponatremia as a high urine output may alert

The correct treatment of hyponatremia in acute the clinician to overly rapid correction of serum Na and the
illness depends first and foremost on the correct diagnosis. serum Na each 4–6 hours with any active treatment until
Applying the above mentioned algorithm, only hypovolemic Na stabilizes.
hyponatremia is appropriately treated by volume expansion The over-correction of hyponatremia is dangerous
with isotonic saline. Therefore, when hypovolemic in patients with cortisol deficiency, or patients receiving
hyponatremia is the suspected diagnosis, a trial of volume desmopressin or thiazides without monitoring of Na,
expansion with isotonic saline is certainly appropriate. If urine osmolality and urine output. Life-threatening
the diagnosis of hypovolemic hyponatremia is correct, the overcorrection can occur in 12 hours.
nonosmotic release of ADH should be suppressed, and the Treatment of SIADH
renal function improves with isotonic saline replacement. Severe or mild-to moderate hyponatremia in SIADH
This corrects the hyponatremia over the next 24–48 h. The must be treated as any other acute hyponatremia with
efficiency of the treatment depends both on the reversibility hypertonic saline infusion, respecting the recommendation
of its cause and the type of its development (acute or described above.
chronic) [8]. Sometimes, in emergency it is difficult to The fluid restriction is recommended as first-line
determine whether the hyponatremia is acute or chronic. therapy in selected patients with chronic hyponatremia
Thus, the severe symptomatic hyponatremia should be provided such patients do not meet the exclusions below.
treated with saline infusion and the patients must be put The typical fluid restriction should be 500 mL/day less than
under surveillance in order to establish the underlying the 24 hour urine output (around 800 ml/day fluid intake).
cause and the onset type. The fluid restriction is forbidden if:
The European Guideline and the American • the urine osmolality is >500 mOsm/kg
Guideline have similar recommendations. They are well • the sum of urinary Na + urinary K >serum Na
summed up in the latest article written by Aylwin et al. [15]. (Furst formula) [17].
Correction of acute hyponatremia • it leads to the discontinuation or delay of needed
Correction of acute severe and symptomatic therapy (surgery, artificial nutrition, i.v. medication,
hyponatremia with infusions of hypertonic saline (3%): chemotherapy etc.).
100 mL over 10 minutes administered up to three times The fluid restriction alone should be discontinued
(or 150 ml in 20 minutes administered 2 times), ideally if the initial Na correction is less than 2 mEq/l in the first
in critical care unit. Acute hyponatremia with mild-to- 24–48 hours. If an effective fluid restriction fails to lead
moderate symptoms should be corrected with 3% NaCl to correction after a few days the diagnosis of euvolemic
(0.5–2 mL/kg/h) infusions and the response should be hyponatremia should be reconsidered.
monitored every 4–6 hours. Some authorities recognize This form of treatment for hyponatremia is often
the use of 1.8% hypertonic saline at 1 mL/kg/hour as an slow and can be difficult for patients to maintain in the long
alternative therapy in acute (and chronic) hyponatremia. term because of hidden liquids in foods and discomfort
The aim is to raise serum Na levels by 4–6 mEq/l in 6 with thirst [18].
hours in acute severe hyponatremia, followed by a pause Medication. The 2014 European Guideline
for 12–24 hours. A small shift in serum sodium is sufficient recommends against the use of vasopressin antagonists for
to reduce intracranial pressure [15]. the treatment of SIADH hyponatremia. The arguments are
Correction of chronic hyponatremia represented by a negative risk/benefit ratio with concern
It is of great importance to stratify for the risk of regarding the toxicity profiles of these drugs [19]. Neither
osmotic demyelination syndrome (ODS): at-risk patients demeclocycline and lithium, have been proven of any
have serum Na<120 mEq/l for >48 hours, and high risk help, so the European Guideline advises against their use
if serum Na<105 mEq/l, or with hypokalemia, alcoholism, for management of any degree of chronic hyponatremia in
malnutrition, or advanced cirrhosis. The correction rate patients with SIADH [6].
should not exceed 4–8 mEq/l per day in low-risk patients Over the ocean, the Guideline updated in 2013,
with chronic SIADH and 4–6 mEq/l/day in patients at high recommend the lowest recommended standard dose of a
risk of ODS. Na overcorrection should be avoided: >8 vasopressin V2-receptor blocker in hyponatremic patients
mEq/l/day in high-risk patients, or >12 mEq/l/day in low- with suspected SIADH without a therapeutic effect of
risk patients [7,15]. The maximal permitted correction is fluid-intake restriction [7]. Empiric V2-receptor antagonist
18 mEq/l in 48 hours period. Sterns’ Safety Rule of Sixes represents a rescue therapy. Low-dose tolvaptan was shown
is an often cited and easily remembered rule emphasizing to significantly improve hyponatremia (by 3–4 mmol/l)
that symptom improvement can be achieved with a Na within 4 days when compared to placebo [20]. Alternatively,
correction of 6 mEq/l (‘six a day makes sense for safety; so conivaptan is approved for SIADH in the United States.
six in six hours for severe Sx and stop’) [16]. Conivaptan selectively targets the V1a and V2 receptors
The clinician should monitor urine output during and can be administered intravenously in patients who are

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unable to take drugs orally [21]. 2013;13(3):291–295.

The UK adopts a similar position regarding the use 6. Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet
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