CONTENTS

• Rapid Reference 🚀
• Why hypernatremia is important in the ICU
• Clinical manifestations
• Causes of hypernatremia
• Evaluation of cause
• Treatment
  • Addressing specific causes
    • Central DI
    • Nephrogenic DI
  • Optimal rate of sodium reduction
  • Free water replacement
• Special situations
  • The hypernatremic patient with volume overload
  • ICU admission isn't required for elderly patients with hypernatremia
  • Dextrose 2.5% in water (D2.5W)
• Podcast
• Questions & discussion
• Pitfalls

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rapid reference

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management of mild hypernatremia that arises in the ICU:

• [#0] If the patient is awake, thirsty, and able to drink – then encourage them to drink water. Otherwise:
• [#1] Determine the target sodium over the next 24 hours:
  • If patient's sodium is between 140-152 mM: target a sodium of 140 mM.
  • If patient's sodium is >152 mM: target a drop of 12 mM from the current value.
• [#2] Calculate the free water required to achieve the target sodium:
  • (a) Calculate the free water deficit using MDCalc or a similar app.
  • (b) Add one liter per day to account for insensible losses.
  • (c) Consider adding additional free water for patients with ongoing free water losses (diarrhea or polyuria).
• [#3] Provide this quantity of water over the next 24 hours:
  • If possible, provide the water via the gut.
  • Otherwise, provide water in the form of intravenous D5W. Follow glucose and treat hyperglycemia as necessary.
• [#4] Check electrolytes q12 hours to ensure adequate reduction in sodium.

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why hypernatremia is important in the ICU

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• Hypernatremia is very common in the ICU. (22762930) It typically develops during ICU admission due to inadequate free water administration (as an iatrogenic complication of critical illness).
• Hypernatremia is not benign:
  • Hypernatremia causes profound thirst. Particularly among intubated patients, this may cause misery and agitation (which may be inappropriately treated with sedatives or antipsychotics).
  • Hypernatremia may cause delirium, thereby increasing the length of ventilation and ICU stay.
• Hypernatremia should always be corrected promptly.
  • Untreated hypernatremia is a hallmark of low-quality, amateur ICU care. (10397213)
  • Hypernatremia usually won't improve on its own (it usually represents a water deficit that will tend to get worse over time).
  • Even mild hypernatremia (e.g. sodium 146-148 mEq/L) may cause discomfort and shouldn't be ignored.

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clinical manifestations of hypernatremia

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Clinical manifestations are more likely due to acute hypernatremia, as opposed to chronic hypernatremia. Severe symptoms usually correlate with an acute rise in sodium to >158 mM. (Irwin 2023) Findings may include:

• Delirium progressing to coma.
• Hyperreflexia, myoclonic jerks, nystagmus. (36578134)
• Weakness.
• Thirst is often the most prominent symptom:
  • This is a normal, expected symptom of hypernatremia.
  • Any patient with a sodium >150 mEq/L who is alert but not thirsty has hypothalamic dysfunction (either structural or functional). (Irwin 2023)

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common causes of hypernatremia

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sodium or potassium administration

• Hypertonic bicarbonate (e.g., multiple ampules given during a code).
• Hypertonic saline.
• Replacement of hypotonic fluid losses with intravenous isotonic fluid.
• Potassium administration for treatment of hypokalemia will to increase sodium concentrations. (Sodium and potassium are exchanged across the cell membrane, so they have an equivalent effect on tonicity.)
• Sodium ingestion (e.g., drinking soy sauce or ocean water).

inadequate free water intake

• Everyone requires ~1 liter/day of water (more if febrile, tachypneic).
• Common causes of inadequate intake:
  • Inability to access and drink water (e.g., debilitated or delirious patients).
  • Failure to provide adequate free water to intubated patients.

increased gastrointestinal water loss

• Vomiting or other gastrointestinal output (e.g., nasogastric tube, fistula).
• Most forms of diarrhea. (But not secretory diarrhea, which tends to produce diarrhea that has a sodium plus potassium concentration similar to plasma.) 
• Osmotic cathartic agents (e.g., lactulose for hepatic encephalopathy).

renal water loss due to central diabetes insipidus

• Intracranial hemorrhage.
• TBI (traumatic brain injury).
• Neurosurgical complication.
• Herniation, brain death.
• Any mass lesion (e.g., brain tumors, aneurysms).
• Infections (meningitis, encephalitis).
• Inflammation, e.g.:
  • Checkpoint inhibitor hypophysitis.
  • IgG4-related hypophysitis.
  • Idiopathic autoimmune hypophysitis.
• Infiltrative diseases, e.g.:
  • Neurosarcoidosis.
  • Langerhans cell histiocytosis.
• GBS (Guillain-Barre syndrome). (36578134)
• Gestational diabetes insipidus. (Vasopressinase secreted by the placenta may degrade maternal vasopressin, thereby causing a vasopressin deficiency that mimics central diabetes insipidus. DDAVP is not degraded, so DDAVP may be utilized to treat this if necessary.)

renal water loss due to diuresis

• Loop diuretics (e.g., furosemide). (They stimulate production of dilute urine, causing a proportionately greater loss of water than of sodium.)
• Mannitol administration.
• Glucosuria:
  • Hyperglycemia.
  • SGLT2 inhibitors.
• Clearance of accumulated urea status post AKI. (Following recovery from acute kidney injury, endogenous urea that has accumulated will finally be excreted, carrying water along with it. This causes hypernatremia, but it is actually a sign of renal recovery.) 

renal water loss due to nephrogenic diabetes insipidus

• Medications:
  • Amphotericin.
  • Cidofovir.
  • Cisplatin.
  • Demeclocycline.
  • Foscarnet.
  • Ifosfamide.
  • Lithium use (chronic):
    • Nephrogenic DI occurs in ~25% of patients on chronic lithium therapy. (36868726)
    • Patients often compensate for partial nephrogenic diabetes insipidus at home by drinking lots of water. If they become incapacitated (e.g., delirious or intubated), they will lose this compensation and develop hypernatremia.
  • Vaptans.
• Hypercalcemia.
• Severe hypokalemia.
• AKI (acute kidney injury) and/or chronic kidney disease often cause impaired urinary concentration, including:
  • Post-ATN polyuria.
  • Postobstructive polyuria.
  • Multiple myeloma, amyloidosis.
  • Sickle cell disease.
  • Sjogren syndrome.

renal sodium retention

• Excess mineralocorticoid activity may cause excessive sodium reabsorption (out of proportion to water absorption).  Usually this only causes a mild hypernatremia.  Causes may include:
  • Primary hyperaldosteronism.
  • Hypercortisolism.
  • Exogenous mineralocorticoids or glucocorticoids. (36868726)

hypothalamic dysfunction (rare)

• [1] Impaired thirst (hypodipsia). This may be treated simply with forced water intake.
• [2] Adipsic diabetes insipidus: Vasopressin secretion only responds to hypovolemia (not changes in tonicity).
• [3] Reset osmostat occurs in patients with primary mineralocorticoid excess, causing the sodium to frequently range between ~141-145 mOsm. This may reflect hypervolemia causing a suppression of vasopressin secretion. (Irwin 2023)

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evaluation of cause

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[1] history and physical examination can often reveal the cause

• Review inputs/outputs:
  • Polyuria (>3 liters/day) suggests the presence of some form of diabetes insipidus or osmotic diuresis.
  • Diarrhea or high-volume gastrointestinal losses?
• Is the patient being provided with adequate free water?
• Are there medications that cause hypernatremia?
  • Amphotericin.
  • Cidofovir.
  • Cisplatin.
  • Foscarnet.
  • Furosemide.
  • Hypertonic saline or hypertonic bicarbonate.
  • Ifosfamide.
  • Lactulose.
  • Lithium.
  • Mannitol.
  • Potassium in high doses.
  • SGLT2 inhibitors.
• Are there specific disease states that cause hypernatremia?
  • Severe hyperglycemia.
  • Active neurological disease (especially brain death).

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[2] laboratory evaluation

• Full electrolytes (including Ca/Mg/Phos).
  • Hypercalcemia or hypokalemia may cause nephrogenic diabetes insipidus.

urine osmolality is the most important test:

• Urine osmolality <300 mOsm suggests complete diabetes insipidus (either nephrogenic or central). This may be suggested by a urine specific gravity <1.010.
• Urine osmolality of ~300-500 mOsm suggests partial diabetes insipidus (either nephrogenic or central).
• Urine osmolality >~600 mOsm: This is a physiologically normal response to hypernatremia. It is compatible with most causes of hypernatremia (other than diabetes insipidus).

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[3] evaluate response to IV DDAVP

A trial of DDAVP may be useful for patients who have urine osmolality below ~500 mOsm in the face of hypernatremia:

• [1] Obtain a baseline urine osmolarity immediately before DDAVP administration.
• [2] Administer 2 micrograms of IV DDAVP once. (This should maximally stimulate renal water reabsorption.)
• [3] Follow:
  • Urine output.
  • Urine osmolality after 2 hours.

potential responses to exogenous DDAVP 

• Nephrogenic DI: DDAVP has no effect:
  • Complete nephrogenic DI: Urine osmolarity remains stable at <300 mOsm.
  • Partial nephrogenic DI: Urine osmolarity remains stable at ~300-500 mOsm.
• Central DI: DDAVP causes a marked increase in urine osmolarity:
  • Complete central DI: Baseline urine osmolarity is <300 mOsm; after DDAVP this increases dramatically (by >200 mOsm, usually to a value >500 mOsm/kg).
  • Partial central DI: Baseline urine osmolarity is ~200-500 mOsm; after DDAVP this increases substantially (by >200 mOsm). (Koyner 2021)

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treatment: addressing specific causes

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The treatment of most causes of hypernatremia consists of general treatment of the underlying disorder and supportive care (e.g., replacement of lost water and electrolytes). The following situations require more advanced management:

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treatment of central diabetes insipidus

Central diabetes insipidus will respond to the replacement of vasopressin activity. However, this may cause patients to retain free water, with a risk of developing hyponatremia. Consequently, close monitoring is required.

treatment options include

• 💡 Less aggressive treatment is required among patients with ad librium access to water (who will be able to compensate for renal water losses by drinking water).
• DDAVP clamp: a high dose of desmopressin (2 micrograms IV q8 hours) will cause the kidneys to retain free water. This is extremely effective for the treatment of hypernatremia. However, if excessive fluid is provided, hyponatremia will occur. Once hypernatremia is controlled, the dose may be decreased to a lower dose that may allow some free water secretion (e.g., 1-2 micrograms IV BID).
• Intranasal DDAVP: the usual dose 10 mcg insufflated twice daily, with a range of 10-40 mcg cumulative daily dose. This may be less potent than intravenous DDAVP, but it has the advantage of potentially representing a long-term treatment strategy.
• Oral DDAVP is available, but this may be suboptimal because oral bioavailability can be variable.
• Vasopressin infusion at 0.001-0.01 units/minute may occasionally be utilized in some situations (e.g., if a vasopressor is required for management of hypotension). This has the advantage that it is titratable, so that it can be stopped if hyponatremia occurs.

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treatment of nephrogenic diabetes insipidus

• Patients may have chronically elevated free water requirements (e.g., chronic nephrogenic diabetes insipidus from lithium). The most important component of management is simply providing enough free water to keep up with losses.
• Thiazide diuretics may be helpful (with the exception of patients who are still taking lithium, who are at risk of volume depletion and increased lithium reabsorption):
  • [1] Mild hypovolemia induced by thiazides stimulates increased water reabsorption in the proximal tubule.
  • [2] Thiazides limit the ability to dilute the urine, causing an increase in urinary osmolarity. (Irwin 2023)
• Amiloride may be used to augment the efficacy of thiazides:
  • Amiloride may augment natriuresis.
  • Amiloride reduces potassium wasting induced by the thiazide diuretic. (Irwin 2023)

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treatment: optimal rate of sodium reduction

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acute hypernatremia (<<48 hours)

• Acute hypernatremia should be corrected rapidly (the brain tissue won't have time to adapt to hypernatremia, so there is no risk of cerebral edema).
• The precise rate of change that is safe is unknown. For patients with neurologic deterioration due to acute hypernatremia, very rapid correction is probably safer than slower correction (leaving the patient with an elevated sodium for a prolonged period could theoretically create a risk of osmotic demyelination!).
  • In one epic case, a 19-year-old man drank a quart of soy sauce and developed acute hypernatremia with sodium 196 mM, seizures, and coma. He was treated with six liters of free water over 30 minutes and recovered well. (23735849)
• For patients with acute hypernatremia and oliguria, hemodialysis may be needed to rapidly correct the sodium (without obligating the patient to receive a large volume of free water).

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chronic hypernatremia (>>48 hours)

basic concepts of chronic hypernatremia

• Brain tissue will adapt to hypernatremia over time. Subsequently, rapidly dropping the sodium concentration could theoretically cause cerebral edema and (if severe) herniation.
• Traditional teaching is to target a sodium decrease of 12 mEq/L per day (0.5 mEq/L/hr). However, some authors recommend twice this rate (1 mEq/L/hr). (24559470) Both choices appear to be equally arbitrary.

chronic hypernatremia in patients over ~40 years old

• There is no evidence that rapid correction of sodium causes harm for most older patients. Retrospective studies actually correlate slower correction of sodium with worse outcomes. (24559470, 21358313)
• There don't appears to be case studies of patients who developed herniation due to over-aggressive sodium correction (unlike overcorrection of hyponatremia, wherein scores of case studies document harm from osmotic demyelination). One case study described a patient whose sodium was dropped by 20 mEq/L in two hours hour by dialysis, without any problems. (25431600)
• Occasional patients may be at elevated risk of cerebral edema (e.g., patients with active neurological disease and pre-existing cerebral edema).
• Bottom line: For patients >>40 years old who don't have active neurologic disease, don't be worried about overshooting 12 mM/day. By far the most common problem is dropping the sodium too slowly.

chronic hypernatremia in patients below ~40 years old

• The risk of cerebral edema is higher among younger people, especially:
  • Very young patients (e.g., ~18-25 years old).
  • Premenopausal women (who have very little empty space in their brains).
• Targeting 12 mM daily reduction could be reasonable for these patients, but this remains largely unknown.

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treatment: free water replacement

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ad librium vs. goal-directed therapy

• The cornerstone of hypernatremia treatment is free water replacement. There are two general strategies to achieve this:
  • Ad librium strategy: For alert patients with mild-moderate hypernatremia who are thirsty and able to drink, the best treatment is to simply provide them with free access to water. This is easy and effective.
  • Goal-directed strategy: For comatose patients or patients with severe hypernatremia, calculation of water needs and monitoring is needed. The remainder of this chapter describes how to do this.

calculate the amount of free water required over 24 hours

• [1] Calculate the amount of free water required to drop from the patient's current sodium to your target sodium over the next day. The target sodium will often be a drop in 12 mM from the current sodium. If the patient's sodium is currently 145-152 mM, then goal may be 140 mM.
  • You are not trying to calculate the total free water deficit here, only what you need to give them in the next 24 hours. For example, the image below shows how to calculate the amount of water required to drop a patient's sodium from 160 mEq/L to 148 mEq/L (using MDCalc).
• [2] Consider adding about one liter in addition to the calculated amount of water, to account for ongoing free water losses.
• [3] For patients with additional ongoing sources of water loss (e.g., active diarrhea), higher initial doses of free water may be appropriate. For patients with ongoing polyuria (>3 liters/day urine output), consider replacing any urinary losses beyond 3 liters/day with an equal volume of free water. (Koyner 2021)

administer free water

• Enteral water administration is the best route, usually via an enteral feeding tube.
• If the enteral route is unavailable, free water should be given as D5W (or possibly D2.5W if that is available ⚡️).

monitor therapy and adjust as needed

• Electrolytes should be monitored (e.g., q12hr).
• Unlike hyponatremia, significant over-correction of hypernatremia is rarely a problem (discussed further below).
• Under-correction will occur if there is ongoing free water loss (e.g., ongoing use of lactulose for the treatment of hepatic encephalopathy). Up-titrate the free water as needed to achieve the target sodium.

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management of the hypernatremic patient with volume overload

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introduction to the hypernatremic patient with volume overload

• Hypernatremia and volume overload are both common in the ICU, so it's not uncommon to see this combination.
• A common cause of this situation is a patient who is admitted with profound volume overload (e.g., 10-20 liters positive). Several liters are diuresed off with furosemide. Furosemide stimulates production of a dilute urine, so this leaves the patient with hypernatremia.
• Inexperienced practitioners may be paralyzed about how to fix this situation:
  • Furosemide will make the hypernatremia worse.
  • Free water will make the volume overload worse.

management of hypernatremia with volume overload

• [1] Diuresis that includes 1-2 natriuretic diuretics to promote the excretion of sodium:
  • Thiazide diuretics are the cornerstone of natriuresis here. The addition of a thiazide diuretic has been shown in an RCT to promote loss of sodium. (26948252)
  • Amiloride will also help promote sodium excretion. The addition of amiloride will additionally help prevent hypokalemia and metabolic alkalosis (which may result from the use of a loop diuretic combined with a thiazide).
  • For example: the diuretic regimen might involve a scheduled oral thiazide diuretic (e.g., indapamide 5 mg daily or metolazone 5 mg BID) plus amiloride (e.g., 10 mg/day) plus furosemide (dosed in titrated IV boluses to achieve the desired diuretic target).
• [2] Aggressive administration of free water (either enteral water or intravenous D5W), based on calculation of the free water deficit as described above.
• [3] Careful monitoring & titration:
  • Monitor input/output balance and titrate furosemide boluses to achieve the desired diuresis target.
  • Monitor electrolytes including magnesium; replete electrolytes as needed.
  • Adjust free water administration to achieve the sodium target.
  • Monitor hemodynamics (e.g., with POCUS) if there is any concern that the patient is reaching euvolemia or hypovolemia.
• (Further discussion of the concept of natriuresis here: 🌊)

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ICU admission isn't needed for elderly patients with hypernatremia

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The most common cause of severe hypernatremia in the emergency department is an elderly patient with dementia who has difficulty eating and drinking. These patients may gradually develop profound hypernatremia (e.g., sodium >170 mEq/L). This will trigger panic and a desire to admit the patient to the ICU. However, ICU admission is generally not needed for these patients for the following reasons.

[1] over-correction of hypernatremia is extremely unlikely

• Hypernatremia in this situation represents a free water deficit.
• Since humans are incapable of generating water, it is unlikely that the patient will suddenly overcorrect (and abruptly drop their sodium level).
  • The only way that over-correction could occur is if the patient abruptly woke up and started drinking lots of water.
• Sodium over-correction is generally seen in hyponatremia, due to rapid excretion of free water. This mechanism cannot occur in patients with hypernatremia due to a water deficit.

[2] overcorrection would be safe

• If overcorrection did occur (e.g., sodium levels falling >12 mEq/L) this would probably be safe.
• As discussed above, there is no evidence that rapid falls in sodium are dangerous in older adults. This is likely to be especially true among the elderly, who often have decreased brain size and thus greater room in which to swell (should edema occur).

reasonable treatment strategy

• [1] Calculate the appropriate volume of free water to achieve a 12 mEq/day drop in sodium (as described above). In severe hypernatremia, the safest way to provide this is either as a continuous infusion of D5W or via gastric tube.
• [2] Check the serum sodium q6-q8 hours and adjust the free water intake appropriately.
• [3] Restrict the patient's intentional water intake to <1 liter per day, to avoid abrupt shifts in sodium.

consider palliative care

• Dehydration is sometimes a mechanism of natural, painless death in an elderly person with severe dementia.
• Prior to resuscitation with water, consider the patient's wishes and baseline quality of life.

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dextrose 2.5% in water (D2.5W)

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• In patients with severe hypernatremia, diabetes, and lack of enteral access it becomes desirable to administer intravenous water with as little dextrose as possible. However, some dextrose is required to increase the osmolarity enough to avoid hemolysis of erythrocytes.
• D5W is only mildly hypotonic (252 mOsm). This is higher than is necessary to prevent hemolysis, so it's providing an unnecessarily large amount of dextrose.
• D2.5W is 126 mOsm, which is only slightly lower than the tonicity of half-normal saline (154 mMosm). If available, D2.5W might be preferable over D5W for the management of hyponatremia. (35212303, 12456462, 26046415) However, there is not a robust evidentiary basis that D2.5W carries zero risk of hemolysis. If there is concern about the low tonicity of D2.5W, then D3W could be compounded (with a tonicity of 151 mOsm, D3W has essentially the same tonicity has half-normal saline). 

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Hypernatremia causes ICU patients to be delirious, thirsty, agitated, and miserable. It requires prompt and definitive management. This is a core competency for anyone managing critically ill patients.
• Hypernatremia should be approached with the same degree of urgency that we would use when treating hyperkalemia.
• If you see a patient's sodium gradually trending upwards, don't wait until it is severely elevated. Free water should be given in anticipation of worsening free water deficiency, to prevent hypernatremia.
• Failure to calculate the free water requirement will usually cause inadequate amounts of water to be delivered. Free water needs are often surprisingly high.
• Routinely providing patients with adequate amounts of free water enterally along with their tube feeds may avoid problems with hypernatremia.
• If a patient with brain injury starts producing large volumes of pale, dilute urine, don't ignore this – check electrolytes and consider the possibility of central diabetes insipidus.

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