Hypernatremia

Hypernatremia results from a net water loss or a sodium gain, and it reflects too little water in relation to total body sodium and potassium. In a simplified view, the serum sodium concentration (Na+) can be seen as a function of the total exchangeable sodium and potassium in the body and the total body water.[5] The formula is expressed below:

Na+ = Na+ total body + K+ total body/total body water

Consequently, hypernatremia can only develop as a result of either a loss of free water or a gain of sodium or a combination of both. Hypernatremia by definition is a state of hyperosmolality, because sodium is the dominant extracellular cation and solute.[6]

The normal plasma osmolality (Posm) lies between 275 and 290 mOsm/kg and is primarily determined by the concentration of sodium salts. (Calculated plasma osmolality: 2(Na) mEq/L + serum glucose (mg/dL)/18 + BUN (mg/dL)/2.8). Regulation of the Posm and the plasma sodium concentration is mediated by changes in water intake and water excretion. This occurs via two mechanisms:

• Urinary concentration (via pituitary secretion and renal effects of the antidiuretic hormone arginine vasopressin [AVP]) ^{[7, 8]}
• Thirst ^[9]

In a healthy individual, thirst and AVP release are stimulated by an increase in body fluid osmolality above a certain osmotic threshold, which is approximately 280-290 mOsm/L and is considered to be similar if not identical for both thirst and AVP release. An increased osmolality draws water from cells into the blood, thus dehydrating specific neurons in the brain that serve as osmoreceptors or “tonicity receptors.” It is postulated that the deformation of the neuron size activates these cells (thus acting like mechanoreceptors). On stimulation, they signal to other parts of the brain to initiate thirst and AVP release, resulting in increased water ingestion and urinary concentration, rapidly correcting the hypernatremic state.

Urinary concentration - AVP and the kidney

Conservation and excretion of water by the kidney depends on the normal secretion and action of AVP and is very tightly regulated. The stimulus for AVP secretion is an activation of hypothalamic osmoreceptors, which occurs when the plasma osmolality reaches a certain threshold (approximately 280 mOsm/kg). At plasma osmolalities below this threshold level, AVP secretion is suppressed to low or undetectable levels. Other afferent stimuli, such as a decrease in effective arterial blood volume, pain, nausea, anxiety, and numerous drugs, can also cause a release of AVP.[10]

AVP is synthesized in specialized magnocellular neurons whose cell bodies are located in the supraoptic and paraventricular nuclei of the hypothalamus. The prohormone is processed and transported down the axon, which terminates in the posterior pituitary gland. From there, it is secreted as active AVP hormone into the circulation in response to an appropriate stimulus (hyperosmolality, hypovolemia).

AVP binds to the V2 receptor located on the basolateral membrane of the principal cells of the renal collection ducts. The binding to this G-protein coupled receptor initiates a signal transduction cascade, leading to phosphorylation of aquaporin-2 and its translocation and insertion into the apical (luminal) membrane, creating "water channels" that enable the absorption of free water in this otherwise water-impermeable segment of the tubular system

Thirst

Thirst is the body’s mechanism to increase water consumption in response to detected deficits in body fluid. As with AVP secretion, thirst is mediated by an increase in effective plasma osmolality of only 2-3%. Thirst is thought to be mediated by osmoreceptors located in the anteroventral hypothalamus. The osmotic thirst threshold averages approximately 288-295 mOsm/kg. This mechanism is so effective that even in pathologic states in which patients are unable to concentrate their urine (diabetes insipidus) and excrete excessive amounts of urine (10-15 L/d), hypernatremia does not develop because thirst is stimulated and body fluid osmolality is maintained at the expense of profound secondary polydipsia.

Developing hypernatremia is virtually impossible if the thirst response is intact and water available. Thus, sustained hypernatremia can occur only when the thirst mechanism is impaired and water intake does not increase in response to hyperosmolality or when water ingestion is restricted.

Significant hypovolemia stimulates AVP secretion and thirst. Blood pressure decreases of 20-30% result in AVP levels many times those required for maximal antidiuresis.

Hypernatremic states can be classified as isolated water deficits (which are generally not associated with intravascular volume changes), hypotonic fluid deficits, and hypertonic sodium gain.

Regulation of brain cell volume

Acute hypernatremia is associated with a rapid decrease in intracellular water content and brain volume caused by an osmotic shift of free water out of the cells. Within 24 hours, electrolyte uptake into the intracellular compartment results in partial restoration of brain volume. A second phase of adaptation, characterized by an increase in intracellular organic solute content (accumulation of amino acids, polyols, and methylamines), restores brain volume to normal. Some patients complete this adaptive response in less than 48 hours. The accumulation of intracellular solutes bears the risk for cerebral edema during rehydration. The brain cell response to hypernatremia is critical. See the image below.

Figure A: Normal cell. Figure B: Cell initially responds to extracellular hypertonicity through passive osmosis of water extracellularly, resulting in cell shrinkage. Figure C: Cell actively responds to extracellular hypertonicity and cell shrinkage in order to limit water loss through transport of organic osmolytes across the cell membrane, as well as through intracellular production of these osmolytes. Figure D: Rapid correction of extracellular hypertonicity results in passive movement of water molecules into the relatively hypertonic intracellular space, causing cellular swelling, damage, and ultimately death.

Several risk factors exist for hypernatremia. The greatest risk factor is age older than 65 years. In addition, mental or physical disability may result in impaired thirst sensation, an impaired ability to express thirst, and/or decreased access to water.[11, 12]

Hypernatremia often is the result of several concurrent factors. The most prominent is poor fluid intake. Again, developing hypernatremia is virtually impossible if the thirst response is intact and water is available. Normally, an increase in osmolality of just 1-2% stimulates thirst, as do hypovolemia and hypotension. For clinical purposes, hypernatremia can, in a simplified view, be classified on the basis of the concurrent water loss or electrolyte gain and on corresponding changes in extracellular fluid volume, as follows:

• Hypotonic fluid deficits (loss of water and electrolytes)
• Nearly pure-water deficits
• Hypertonic sodium gain (gain of electrolytes in excess of water).

Loss of hypotonic fluid (loss of water in excess of electrolytes)

Patients who lose hypotonic fluid have a deficit in free water and electrolytes (low total body sodium and potassium) and have decreased extracellular volume. In these patients, hypovolemia may be more life-threatening than hypertonicity. When physical evidence of hypovolemia is present, fluid resuscitation with normal saline is the first step in therapy.

Renal hypotonic fluid loss results from anything that will interfere with the ability of the kidney to concentrate the urine or osmotic diuresis, such as the following:

• Diuretic drugs (loop and thiazide diuretics)
• Osmotic diuresis (hyperglycemia, mannitol, urea [high-protein tube feeding])
• Postobstructive diuresis
• Diuretic phase of  acute tubular necrosis

Nonrenal hypotonic fluid loss can result from any of the following:

• GI - Vomiting, diarrhea, lactulose, cathartics, nasogastric suction, gastrointestinal fluid drains, and fistulas
• Cutaneous - Sweating (extreme sports, marathon runs), burn injuries

Pure-water deficits

Patients with pure-water deficits in the majority of cases have a normal extracellular volume with normal total body sodium and potassium. This condition most commonly develops when impaired intake is combined with increased insensible (eg, respiratory) or renal water losses.

Free-water loss will also result from an inability of the kidney to concentrate the urine. The cause of that can be either from failure of the hypothalamic-pituitary axis to synthesize or release adequate amounts of AVP (central diabetes insipidus) or a lack of responsiveness of the kidney to AVP (nephrogenic diabetes insipidus). Patients with diabetes insipidus and intact thirst mechanisms most often present with normal plasma osmolality and serum NA+, but with symptoms of polyuria and polydipsia.

Water intake less than insensible losses may result from any of the following:

• Lack of access to water (through incarceration, restraints, intubation, immobilization)
• Altered mental status (through medications, disease)
• Neurologic disease (dementia, impaired motor function)
• Abnormal thirst (eg, geriatric hypodipsia; osmoreceptor dysfunction (reset of the osmotic threshold); injury to the thirst centers by any lesions to the hypothalamus, including from metastasis, granulomatous diseases, vascular abnormalities, and trauma; autoantibodies to the sodium-level sensor (Na _x) in the brain ^[13]
• Loss of water through the respiratory tract

Vasopressin (AVP) deficiency (diabetes insipidus)

Central diabetes insipidus[14]  can be caused by any pathologic process that destroys the anatomic structures of the hypothalamic-pituitary axis involved in AVP production and secretion. Such processes include the following:

• Pituitary injury - Posttraumatic, neurosurgical, hemorrhage, ischemia (Sheehan’s), idiopathic-autoimmune, lymphocytic hypophysitis, IgG4-related disease
• Tumors - Craniopharyngioma, pinealoma, meningioma, germinoma, lymphoma, metastatic disease, cysts
• Aneurysms - Particularly anterior communicating
• Inflammatory states and granulomatous disease - Acute meningitis/encephalitis, Langerhans cell histiocytosis, neurosarcoidosis, tuberculosis
• Drugs - Ethanol (transient), phenytoin
• Genetic - Neurophysin II ( AVP carrier protein) gene defect

Nephrogenic diabetes insipidus (decreased responsiveness of the kidney to vasopressin)

Causes include the following:

• Genetic - V2-receptor defects, aquaporin defects (AQP2 and AQP1); 90% by  AVPR2 mutations (X-liked recessive),  AQP2 gene mutation ^[15]
• Structural - Urinary tract obstruction, papillary necrosis, sickle-cell nephropathy
• Tubulointerstitial disease - Medullary cystic disease, polycystic kidney disease, nephrocalcinosis, Sjögren’s syndrome, lupus, analgesic-abuse nephropathy, sarcoidosis, M-protein disease, cystinosis, nephronophthisis
• Others - Distal renal tubular acidosis, Bartter syndrome, apparent mineralocorticoid excess ^[16]
• Electrolyte disorders - Hypercalcemia,  hypokalemia
• Any prolonged state of severe polyuria - By washing out the renal medullary- intramedullary concentration gradient needed for urinary concentration, and by down-regulating kidney AQP2 water channels (partial diabetes insipidus)
• Medications

Medications that induce nephrogenic diabetes insipidus include the following:

• Lithium (40% of patients)
• Amphotericin B
• Demeclocycline
• Dopamine
• Ofloxacin
• Orlistat
• Ifosfamide

Medications that possibly cause nephrogenic diabetes insipidus include the following:

• Contrast agents
• Cyclophosphamide
• Cidofovir
• Ethanol
• Foscarnet
• Indinavir
• Libenzapril
• Mesalazine
• Methoxyflurane
• Pimozide
• Rifampin
• Streptozocin
• Tenofovir
• Triamterene hydrochloride
• Colchicine

Adipsic diabetes insipidus (central diabetes insipidus with deficient thirst)

This is caused by a combination of damage to the osmoreceptors regulating thirst sensation and central diabetes insipidus (see above).[17]  Etiologies include the following:

• Congenital conditions (septo-optic dysplasia, germinoma)
• Vascular (anterior communicating artery aneurysm clipping/rupture)
• Others - Craniopharyngioma, pinealoma, Langerhans cell histiocytosis, neurosarcoidosis, head trauma, cytomegalovirus encephalitis

Gestational diabetes insipidus

In this form of diabetes insipidus, AVP is rapidly degraded by a high circulating level of oxytocinase/vasopressinase. It is a rare condition, because increased AVP secretion will compensate for the increased rate of degradation. Gestational diabetes insipidus occurs only in combination with impaired AVP production.

Hypertonic sodium gain

Patients with hypertonic sodium gain have a high total-body sodium and an extracellular volume overload (rare, mostly iatrogenic). When thirst and kidney function are intact, this condition is transient. Causes include the following:

• Administration of hypertonic electrolyte solutions - Eg, sodium bicarbonate solutions, hypertonic alimentation solutions, normal saline with or without potassium supplements
• Sodium ingestion - NaCl tablets, seawater ingestion
• Sodium modeling in hemodialysis

Water shift (transient)

Water shifts into muscle cells during extreme exercise or seizures because of increased intracellular osmoles). In clinical practice, a combination of the two may be present. For example, an intubated patient in the ICU develops hypernatremia due to hypertonic sodium gain caused by normal saline volume resuscitation and, in addition, increased free water excretion due to recovering kidney injury and/or osmotic urea-diuresis caused by high-protein tube feeding.

The prevalence of hypernatremia in hospitalized patients has been reported as 1-4%. Analysis by Arzhan et al of data on 1.9 million adult patients from a United States hospital database determined that 3% had serum sodium > 145 mEq/L on samples drawn within 24 hours of admission.[18] Patients with community-acquired hypernatremia were older, had worse kidney function at presentation, and disproportionately suffered from acute infectious illness (eg, urinary tract infection, pneumonia, sepsis).[19]

In contrast, a review by Tsipotis et al of hypernatremia (defined as a serum sodium > 142 mEq/L) in 19,072 unselected hospitalized adults found that 21% had community-acquired hypernatremia, and hospital-acquired hypernatremia developed in 25.9%.[20] At the other extreme, a Korean study of 79,998 hospitalized patients found that only 0.2% had community-acquired hypernatremia (defined as > 147 mEq/L).[21]

A retrospective, single-center study from Austria, which included 981 patients, reported that 2% of patients had hypernatremia on admission to the intensive care unit (ICU) and 7% developed hypernatremia during their stay in the ICU.[22]  Analysis of data on 8140 patients from 12 French ICUs found that 11.1% developed mild hypernatremia and 4.2% developed moderate to severe hypernatremia 24 hours or more after ICU admission.[20]

A Canadian study of 8142 adult patients identified ICU-acquired hyponatremia in 11% of them and ICU-acquired hypernatremia in 26% of these patients.[23] The report found that the mortality rate in patients with ICU-acquired hyponatremia or hypernatremia was greater than that of study patients with normal serum sodium levels, being 28% versus 16% (P <   0.001), and 34% versus 16%, p < 0.001, respectively.

Arzhan et al reported an in-hospital mortality rate of 12% in hypernatremic patients, compared with a 2% incidence in patients with normal sodium levels. In patients with severe hypernatremia (serum sodium > 155 mEq/L), the odds ratio for in-hospital mortality was 34. At all levels of hypernatremia, odds of in-hospital mortality were higher in patients older than 75 years.[18]

The groups most commonly affected by hypernatremia are elderly people and children.[24] In breastfed neonates, insufficient milk intake can result in dehydration and hypernatremia.[25, 26]

In patients with community-acquired hpernatremia, Tsipotis et al reported an adjusted odds ratio (OR) of 1.67 (95% confidence interval [CI], 1.38-2.01) for in-hospital mortality and 1.44 (95% CI, 1.32-1.56) for discharge to a short-/long-term care facility and an adjusted 10% (95% CI, 7-13) increase in length of stay. Patients with hospital-acquired hypernatremia had an adjusted OR of 3.17 (95% CI, 2.45-4.09) for in-hospital mortality and 1.45 (95% CI, 1.32-1.59) for discharge to a facility, and an adjusted 49% (95% CI, 44-53) increase in length of stay.[20]

Mortality rates of 30-48% have been shown in patients in ICUs who have serum sodium levels exceeding 150 mmol/L.[27, 28]  A review of 256 patients presenting to a Turkish emergency department with severe hypernatremia (serum sodium >160 mmol/L) determined that the following factors were independently associated with mortality[29] :

• Low systolic blood pressure
• Low pH
• Serum sodium > 166 mmol/L
• Increased plasma osmolarity
• Mean sodium reduction rate of 0.134 mmol/L/h or less
• Dehydration
• Pneumonia

Comparing hospital mortality rates for the patients without hypernatremia with those for cohort members with the condition, Darmon et al determined that the subdistribution hazard ratio for mortality from ICU-acquired hypernatremia was 2.03 for mild hypernatremia and 2.67 for moderate–to-severe hypernatremia.[27]  However, whether the association of ICU-acquired hypernatremia with an increased risk for death reflects a direct effect of hypernatremia or is a marker for suboptimal quality of care is uncertain.

One study confirmed that maximum daily sodium amount is a significant risk factor for the development of acute kidney injury in patients with subarachnoid hemorrhage (SAH) who are receiving hypertonic saline therapy. Such therapy is often used to control intracranial hypertension and manage symptomatic hyponatremia. Of 736 patients in one study, 9% (64) developed acute kidney injury. For each 1 mEq/L increase in the running maximum daily serum sodium rate, the risk of developing acute kidney injury increased by 5.4 %, and the risk of death was more than twofold greater for patients who developed acute kidney injury.[30]

Early acquired hypernatremia in the ICU has been found to be a frequent complication in patients with severe sepsis and is associated with the volume of 0.9% saline received during the first 48 hours of admission in the ICU. In one study, of 95 patients with severe sepsis, 29 (31%) developed hypernatremia within 5 days. For every 50 ml/kg increase in 0.9% saline intake during the first 48 hours, the odds of hypernatremia increased by 1.61 times. Patients who developed hypernatremia had increased duration of mechanical ventilation and increased mortality.[31]

According to a study by Leung et al, preoperative hypernatremia is associated with increased perioperative 30-day morbidity and mortality. In their study, 20,029 patients with preoperative hypernatremia (>144 mmol/L) were compared with 888,840 patients with a normal baseline sodium (135-144 mmol/L). The odds of morbidity and mortality increased according to the severity of hypernatremia (P < 0.001 for pairwise comparison for mild [145-148 mmol/L] vs severe [>148 mmol/L] categories). Hypernatremia, versus normal baseline sodium, was associated with a greater odds for perioperative major coronary events (1.6% vs 0.7%), pneumonia (3.4% vs 1.5%), and venous thromboembolism (1.8% vs 0.9%).[32]

Treatment-resistant hypernatremia has been reported in patients with severe COVID-19. Zimmer et al found no correlation between plasma sodium concentrations and sodium input in these patients, along with elevations in plasma chloride concentrations and decreases in potassium—findings consistent with an abnormal increase in renal sodium reabsorption, possibly caused by increased angiotensin II activity secondary to virally induced downregulation of angiotensin-converting enzyme 2 (ACE2) receptors.[33] Hypernatremia in COVID-19 has been associated with the need for ventilator support, increased length of ICU stay, sepsis, altered mental status, and high mortality.[34, 35, 36]   

Patients developing hypernatremia outside of the hospital setting are generally elderly and debilitated, and often present with an intercurrent acute (febrile) illness. Hospital-acquired hypernatremia affects patients of all ages.

The history should be used to discover why the patient was unable to prevent hypernatremia with adequate oral fluid intake. For example, the clinician should determine whether the patient is suffering from an altered mental status or whether there are any factors causing increased fluid excretion (eg, diuretic therapy; diabetes mellitus; or fever, diarrhea, and vomiting). The history should also cover the symptoms and causes of possible diabetes insipidus (eg, the presence of preexisting polydipsia or polyuria, a history of cerebral pathology, or medication use [lithium]).

It is important to find out if the hypernatremia developed acutely or over time, because this will guide treatment decisions.

Risk factors for hypernatremia include the following:

• Advanced age
• Mental or physical impairment
• Uncontrolled diabetes (solute diuresis)
• Underlying polyuria disorders
• Diuretic therapy
• Residency in nursing home, inadequate nursing care
• Hospitalization ^{[27, 37]}

Hospitalized patients may develop hypernatremia because of any of the following:

• Decreased baseline levels of consciousness
• Tube feeding
• Hypertonic infusions
• Osmotic diuresis
• Lactulose
• Mechanical ventilation
• Medication (eg, diuretics, sedatives)

The examination should include an accurate assessment of volume status and cognitive function. Symptoms can be related to volume deficit and/or hypertonicity and shrinkage of brain cells, which can tear cerebral blood vessels in severe cases, leading to cerebral hemorrhage.

The worsening symptoms associated with hypernatremia may go unnoticed in elderly patients who have a preexisting impairment of their mental status and decreased access to water.

Table 1. Characteristics and symptoms of hypernatremia (Open Table in a new window)

In a prospective, case-control, multicenter study, Chassagne and colleagues looked at the symptoms associated with hypernatremia in 150 geriatric patients.[38]  The likelihood that patients with hypernatremia would have low blood pressure, tachycardia, dry oral mucosa, abnormal skin turgor, and a recent change in consciousness was significantly greater than that of the controls. The only clinical findings to occur in at least 60% of patients with hypernatremia were orthostatic blood pressure and abnormal subclavicular and forearm skin turgor (poor specificity and sensitivity for all physical findings).

The diagnosis of hypernatremia is based on an elevated serum sodium concentration (Na+ >145 mEq/L). In addition, the following lab studies are used to determine the etiology of hypernatremia:

• Serum electrolytes (Na ⁺, K ⁺, Ca ^{2 +})
• Glucose level
• Urea
• Creatinine
• Urine electrolytes (Na ⁺, K ⁺)
• Urine and plasma osmolality
• 24-hour urine volume
• Plasma arginine vasopressin (AVP) level (if indicated)

The first step in the diagnostic approach is to estimate the volume status (intravascular volume) of the hypernatremic patient. The associated volume contraction may be mirrored in a low urine Na+ (usually < 10 mEq/L).

In the hypovolemic patient, a hypertonic urine (urine osmolality usually greater than 600 mOsm/kg) with a low UNa+ (usually less than 10–20 mEq/L) will point toward extrarenal fluid losses (eg, gastrointestinal, dermal), whereas an isotonic or hypotonic urine (urine osmolality 300 mOsm/kg or less) with a UNa+ higher than 20–30 mEq/L indicates renal fluid loss (eg, from diuretics, osmotic diuresis, intrinsic renal disease).

In the euvolemic patient with preserved intravascular volume, hypernatremia is most likely due to pure-water losses. In the presence of hypernatremia, urine osmolality normally should be maximally concentrated (>800 mOsm/kg H2O). Measurement of the urine osmolality will allow differentiation of the following:

• Nonrenal causes with appropriately high urine osmolality - Isolated hypodipsia, increased insensible losses
• Renal water loss indicated by inappropriately low urine osmolality - Diabetes insipidus (often U _osm< 300 mOsm/kg H ₂O [central, nephrogenic, partial, gestational diabetes insipidus])

Caveat: Unfortunately, concentrating ability tends to fall with age; the maximum Uosm in an elderly patient may be only 500-700 mOsm/kg.

To distinguish between central and nephrogenic diabetes insipidus, first obtain a plasma AVP level and then determine the response of the urine osmolality to a dose of AVP (or preferably, the V2-receptor agonist DDAVP). Generally, an increase in urine osmolality of greater than 50% reliably indicates central diabetes insipidus, while an increase of less than 10% indicates nephrogenic diabetes insipidus; responses between 10% and 50% are indeterminate. Hyperosmolar patients with an elevated AVP level have nephrogenic diabetes insipidus; those with central diabetes insipidus will have inadequately low AVP level.

If the patient has polyuria without hypernatremia and will be evaluated for diabetes insipidus, the plasma sodium has to be above 145 mOsm/kg H2O prior to testing (via water deprivation test, hypertonic saline).

Calculating the free-water clearance (cH2O), which measures the amount of solute-free water excreted by the kidney, is usesful. However, this includes all osmoles, including urea, which does not contribute to the plasma tonicity because it freely equilibrates across cell membranes. To more accurately assess the effect of the urine output on osmoregulation, calculate the electrolyte–free-water clearance (cH2Oe), to estimate the ongoing renal losses of hypotonic fluid (cH2O = Vurine [1-(UOsm/SOsm)]; cH2Oe = Vurine [1-(UNa +UK)/SNa])

An example of the use of he above calculations is as follows: An 80-year-old, partially demented man with poor nutritional status is admitted to the hospital because of pneumonia. Hyperalimentation with high protein supplementation is started (containing 30 mEq/L each of Na+ and K+). Laboratory results over the ensuing 5 days are as follows:

• Urine output: 4 L/day
• BUN: 20-88 mg/dL
• Cr: Stable at 1.4 mg/dL
• [Na ⁺]: From 140 mEq/L up to 156 mEq/L (despite a relatively high fluid intake)
• Posm: 342 mOsm/kg
• Uosm: 510 mOsm/kg
• UNa ⁺: 10 mEq/L
• UK ⁺: 42 mEq/L

The free-water clearance is calculated as follows:

cH2O = 4 x ( 1 - [510 ÷ 342] ) = –2 L/day

By this calculation, taking all osmoles into account, the patient retains 2 liters of water, improving hypernatremia; however, he is actually getting worse.

The electrolyte free-water clearance is calculated as follows:

eCH2O = 4 (1 - [(10 + 41) ÷ 156] ) = 2.7 L/day

The etiology of the hypernatremia is now apparent; the patient is losing approximately 2.7 L of free water per day in his urine, likely secondary to osmotic urea diuresis caused by hyperalimentation.

A magnetic resonance imaging (MRI) or computed tomography (CT) scan of the brain may be helpful in cases of central diabetes insipidus eventuating from head trauma or infiltrative lesions.

Histologic findings usually are noncontributory (although they may be helpful in central diabetes insipidus).

The goals of management in hypernatremia are as follows[39] :

1. Recognition of the symptoms, when present
2. Identification of the underlying cause(s)
3. Correction of volume disturbances
4. Correction of hypertonicity

Correcting the hypertonicity requires a careful decrease in serum sodium and plasma osmolality with the replacement of free water, either orally or parenterally. The rate of sodium correction depends on how acutely the hypernatremia developed and on the severity of symptoms.

Acute symptomatic hypernatremia, defined as hypernatremia occurring in a documented period of less than 24 hours, should be corrected rapidly. With chronic hypernatremia (> 48 h), established practice is to correct more slowly due to the risks of brain edema during treatment. The brain adjusts to and mitigates chronic hypernatremia by increasing the intracellular content of organic osmolytes. The concern is that if extracellular tonicity is rapidly decreased, water will move into the brain cells, producing cerebral edema, which may lead to herniation, permanent neurologic deficits, and myelinolysis.

However, a study by Chauhan et al found no evidence that rapid correction of hypernatremia is associated with a higher risk for mortality, seizure, alteration of consciousness, and/or cerebral edema in critically ill adult patients with hypernatremia. The study included 122 patients with serum sodium concentrations > 155 mEq/L on hospital admission and 327 patients whose serum sodium rose to > 155 mEq/L during hospitalization; 128 of the cases of hospital-acquired hypernatremia were considered chronic, because the disturbance developed over > 48 hours.[40]

In-hospital 30-day mortality rates were comparable with rapid (> 0.5 mmol/L per hour) and slower (≤0.5 mmol/L per hour) correction rates in patients with hypernatremia at admission (25% versus 28%, respectively; P=0.80) as well as in patients with hospital-acquired hypernatremia (44% versus 40%, respectively; P=0.50). The adjusted odds ratio (aOR) of mortality with rapid versus slow correction was the same (1.3) in both admission and hospital-acquired hypernatremia. Chart review did not reveal a single case of cerebral edema attributable to rapid hypernatremia correction.[40]

An accompanying editorial by Sterns points out that the recommendations for the slow correction of hypernatremia are derived from the pediatric literature, which contains reports of rehydration seizures due to cerebral edema infants with hypertonic dehydration. Those reports confirmed the safety of a correction rate ≤12 mEq/L per day for dehydrated infants, but never defined a precise harmful rate.[41]

Chauhan et al note that two previous studies of hypernatremia in adults reported a higher risk of mortality with excessively slow rates of sodium correction and lower mortality with a greater reduction rate.[40]

Treatment recommendations for symptomatic hypernatremia

Recommendations are as follows:

• Establish documented onset (acute, < 24 h; chronic, >24h)
• In acute hypernatremia, correct the serum sodium at an initial rate of 2-3 mEq/L/h (for 2-3 h) (maximum total, 12 mEq/L/d).
• Measure serum and urine electrolytes every 1-2 hours
• Perform serial neurologic examinations and decrease the rate of correction with improvement in symptoms
• Chronic hypernatremia with no or mild symptoms should be corrected at a rate not to exceed 0.5 mEq/L/h and a total of 8-10 mEq/d (eg, 160 mEq/L to 152 mEq/L in 24 h).
• If a volume deficit and hypernatremia are present, intravascular volume should be restored with isotonic sodium chloride prior to free-water administration.

Estimation of the replacement fluid

Total body water (TBW) refers to the lean body weight of the patient (percentage of TBW decreases in morbidly obese patients). The TBW deficit in the hyperosmolar patient that needs to be replaced can be roughly estimated using the formula following formula:

TBW deficit = correction factor × premorbid weight × (1 - 140/Na+)

Ongoing losses (insensible, renal) need to be added.

However, the formulae below, by Adrogué–Madias, are preferred over the conventional equation for water deficit, because the older equation underestimates the deficit in patients with hypotonic fluid loss and is not useful in situations in which sodium and potassium must be used in the infusate. Formulas used to manage hypernatremia are outlined below.

Equation 1: TBW = weight (kg) x correction factor

Correction factors are as follows:

• Children: 0.6
• Nonelderly men: 0.6
• Nonelderly women: 0.5
• Elderly men: 0.5
• Elderly women: 0.45

Equation 2: Change in serum Na+ = (infusate Na+ - serum Na+) ÷ (TBW + 1)

Equation 3: Change in serum Na+ = ([infusate Na+ + infusate K+] – serum Na+) ÷ (TBW + 1)

Equation 2 allows for the estimation of 1 L of any infusate on serum Na+ concentration. Equation 3 allows for the estimation of 1 L of any infusate containing Na+ and K+ on serum Na+.

Common infusates and their Na+ contents include the following:

• 5% dextrose in water (D5W): 0 mmol/L
• 0.2% sodium chloride in 5% dextrose in water (D ₅ 2NS): 34 mmol/L
• 0.45% sodium chloride in water (0.45NS): 77 mmol/L
• Ringer's lactate solution: 130 mmol/L
• 0.9% sodium chloride in water (0.9NS): 154 mmol/L

An example of the use of the above calculations is as follows: An obtunded 80-year-old man is brought to the emergency room with dry mucous membranes, fever, tachypnea, and a blood pressure of 134/75 mm Hg. His serum sodium concentration is 165 mmol/L. He weighs 70 kg. This man is found to have hypernatremia due to insensible water loss.

The man's TBW is calculated by the following:

(0.5 × 70) = 35 L

To reduce the man's serum sodium, D5W will be used. Thus, the retention of 1 L of D5W will reduce his serum sodium by (0 - 165) ÷ (35 + 1) = -4.6 mmol. The goal is to reduce his serum sodium by no more than 10 mmol/L in a 24-hour period. Thus, (10 ÷ 4.6) = 2.17 L of solution is required. About 1-1.5 L will be added for obligatory water loss to make a total of up to 3.67 L of D5 W over 24 hours, or 153 cc/h.

A clinically important study by Lindner and colleagues found that all the above formulae correlated significantly with measured changes in serum sodium in the patient cohort as a whole, but the individual variations were extreme.[42] Thus, although the above formulae can guide therapy, serial measurements of serum sodium are prudent. That finding is no surprise, considering that interindividual variables make it difficult to precisely estimate the individual TBW and its distribution in different body compartments.[43] For example, the degree to which interindividual differences in body fat percentage affect TBW is very large.[4]

Other treatment considerations

If hypernatremia is accompanied by hyperglycemia with diabetes, take care when using a glucose-containing replacement fluid. However, the appropriate use of insulin will help during correction.

In hypervolemic and hypernatremic patients in the ICU who have an impaired renal excretion of sodium and potassium (eg, after renal failure) an addition of a loop diuretic to free water boluses increases renal sodium excretion. Fluid loss during loop diuretic therapy must be restored with the administration of fluid that is hypotonic to the urine.

Use of thiazide diuretics to enhance sodium excretion has been suggested as a treatment for hypernatremia acquired in the ICU. However, a randomized, placebo-controlled trial in 50 ICU patients found that hydrochlorothiazide, 25 mg/day for up to 7 days, did not have a significant effect on serum or urinary sodium concentration.[44]

Hypernatremia in the setting of volume overload (eg, heart failure and pulmonary edema) may require dialysis for correction.

Although water can be replaced by oral and parenteral routes, an obtunded patient with a large free water deficit likely requires parenteral treatment. If the deficit is small and the patient is alert and oriented, oral correction may be preferred.

Once hypernatremia is corrected, efforts are directed at treating the underlying cause of the condition. Such efforts may include free access to water and better control of diabetes mellitus. In addition, correction of hypokalemia and hypercalcemia as etiologies for nephrogenic diabetes insipidus may be required. Vasopressin (AVP, DDAVP) should be used for the treatment of central diabetes insipidus. 

Inpatient care is appropriate only as it relates to the correction of underlying diseases that may lead to hypernatremia (diabetes mellitus). Transfer may only be necessary in the setting of severe head trauma with central diabetes insipidus.

Surgical treatment may be required in the setting of severe central nervous system trauma and associated central diabetes insipidus.

Consultations include the following:

• Neurosurgeon (head trauma)
• Endocrinologist (diabetes insipidus or diabetes mellitus)
• Nephrologist (nephrogenic etiologies for hypernatremia)

Diet should be altered as applicable to diabetes mellitus and need for increased water intake during increased insensible loss. A low-sodium diet will reduce oral solute intake and therefore diminish renal water loss.

Activity alterations are applicable only as related to free access to water.

The Society for Endrocrinology has issued guidelines for the inpatient management of cranial [central] diabetes insipidus (CDI) which include the following recommendations for the management of hypernatremia[45] : 

• Patients with CDI and impaired consciousness or who are unable to manage own fluid intake should have fluid status assessed at least every 12 hours, with fluid input and urine output monitoring and measurement of serum sodium.
• Patients with intercurrent illness or decompensated CDI should receive urgent clinical assessment of volume and hydration status and measurement of serum sodium and potassium and kidney function.Hypernatremia should be managed as a medical emergency. Serum sodium should be measured every 4 hours during fluid resuscitation, reducing to no less frequently than every 12 hours until the patient is clinically and biochemically stable. Patients with high urine output with low urine osmolality require desmopressin (DDAVP).
• Fluid replacement optimization is the first priority, followed by need assessement for DDAVP.
• The type and volume of fluid replacement should be a combination of the standard daily fluid and electrolyte requirement with a component of the estimated fluid deficit.
• Avoid overcorrection of hypernatremia:  For acute hypernatremia, serum sodium should be corrected at a rate of 5 mmol/L in the first hour (or until symptoms improve) and is limited to 10 mmol/L per 24 h. For asymptomatic or mild hypernatremia, serum sodium corrections should not exceed 0.5 mmol/Lhr and is limited to 10 mmol/L per 24 h

Some patients with nephrogenic diabetes insipidus—particularly those in whom it is mild or incomplete—may benefit from diuretic therapy (eg, thiazides, loop-diuretics) in an effort to increase proximal tubular reabsorption and decrease delivery to diluting segments where water may be lost. Inhibition of cyclooxygenase by nonsteroidal anti-inflammatory drugs (NSAIDs) may attenuate the polyuria in these patients. In addition, any medications that may cause nephrogenic diabetes insipidus (such as lithium) may require discontinuation.

In patients with central diabetes insipidus, desmopressin administered orally or intranasally may be used. Pharmacologic agents can be used in partial central diabetes insipidus to increase circulating AVP. These drugs include chlorpropamide, clofibrate, and carbamazepine.

Class Summary

These drugs may be used to enhance sodium excretion.

Hydrochlorothiazide (Esidrix, HydroDiuril, Microzide)

Inhibits the reabsorption of sodium in the distal tubules, causing increased excretion of sodium and water, as well as of potassium and hydrogen ions.

Furosemide (Lasix)

Loop diuretic that increases excretion of water by interfering with chloride-binding cotransport system, which in turn inhibits sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule. Increases renal blood flow without increasing filtration rate. Onset of action generally is within 1-h. Increases potassium, sodium, calcium, and magnesium excretion.

Class Summary

These agents may enhance sodium excretion.

Desmopressin (DDAVP)

Increases cellular permeability of collecting ducts, resulting in the reabsorption of water by the kidneys.