Physical Address

304 North Cardinal St.
Dorchester Center, MA 02124

Hypernatremia


Introduction

Hypernatremia is defined as a concentration of sodium (Na + ) ions in plasma (P Na ) that is greater than 145 mmol/L. Hypernatremia is not a diagnosis; rather it is a laboratory finding that may be the result of a number of disorders of diverse etiology. Hence, one must determine its underlying cause. The first step in the clinical approach to the patient with hypernatremia is to deal with emergencies and to anticipate and prevent dangers that may arise because of therapy. Because the intracellular fluid (ICF) volume is inversely related to the P Na , acute hypernatremia is associated with a decrease in the size of cells in the body. The organ that is most adversely affected is the brain, because as its volume shrinks, vessels coming from the inner surface of the skull become stretched and thus they may rupture, leading to focal intracerebral and subarachnoid hemorrhages. In patients with chronic hypernatremia, cells in the brain gain effective osmoles. Although it is uncertain when this adaptive response is completed, it is estimated that it takes about 48 hours for the brain to accumulate enough effective osmoles to return their volume close to their normal. After this occurs, the danger for the patient is a rapid decrease in the P Na because this may cause these cells to swell. This may result in a rise in intracranial pressure, which may lead to permanent neurological damage or even death caused by herniation of the brain.

Abbreviations

  • DI, diabetes insipidus

  • P Effective osm , effective plasma osmolality

  • PCT, proximal convoluted tubule

  • DCT, distal convoluted tubule

  • MCD, medullary collecting duct

  • EABV, effective arterial blood volume

  • ENaC, epithelial sodium channel

  • ECF, extracellular fluid

  • ICF, intracellular fluid

  • P Na , the concentration of sodium (Na + ) ions in plasma

  • dDAVP, 1-deamino 8- d -arginine vasopressin

  • BUN, blood urea nitrogen

  • P Urea , concentration of urea in plasma

  • DKA, diabetic ketoacidosis

  • P K , concentration of potassium (K + ) ions in plasma

  • U Osm , urine osmolality

  • U Na , concentration of Na + ions in the urine

  • U K , concentration of K + ions in the urine

  • AQP, aquaporin water channel

  • P Osm , plasma osmolality

The next step in the clinical approach is to examine for the presence of the expected responses in this setting, which are the sensation of thirst and the release of vasopressin leading to the excretion of the smallest volume of urine with the highest concentration of effective osmoles.

Hypernatremia that develops outside the hospital is usually caused by a large deficit of water. Although patients who develop hypernatremia in the hospital may also have a deficit of water, in many cases hypernatremia is caused in large part by a positive balance of Na + ions. In some patients with hypernatremia, there is a deficit of both Na + ions and water, with a proportionately larger deficit of water than of Na + ions.

The issues for therapy in the patient with hypernatremia are similar in principle to those that were discussed in patients with hyponatremia in Chapter 10 . If the rise in the P Na has occurred over a time period of less than 48 hours, the P Na should be lowered rapidly if there are severe symptoms that could be related to hypernatremia. In patients with chronic hypernatremia, one should not permit the P Na to fall by more than 8 mmol/L/24 hr.

It is important to stress that there are times when the development of hypernatremia can be beneficial. For example, in children with diabetic ketoacidosis (DKA), it is important to prevent an appreciable fall in the effective osmolality in plasma (P Effective osm ) during the first 15 hours of treatment because a fall in P Effective osm may be a risk factor for the development of cerebral edema, and most cases occur 3-13 hours after therapy is instituted. Therefore, the design of therapy should be such that the P Na should rise by about one half the fall in the concentration of glucose in plasma (P Glucose ) because both Na + ions and their accompanying anions contribute to the P Effective osmolality. Therefore, a degree of hypernatremia may develop, but it should be viewed as beneficial in this setting (see Chapter 5 for more discussion).

Objectives

  • ▪

    To emphasize that hypernatremia represents an increase in the amount of Na + ions relative to the volume of water in the extracellular fluid (ECF) compartment. Hypernatremia can be primarily caused by a negative balance for water or a positive balance for Na + ions. For hypernatremia to develop, however, there must be a defect in sensing thirst, communicating the desire for water, and/or an inability to obtain water.

  • ▪

    To emphasize that the danger to the patient with hypernatremia depends on whether the disorder is acute (duration for the development of hypernatremia <48 hours) or chronic (duration for the development of hypernatremia >48 hours).

  • ▪

    To provide a diagnostic approach to the patient with hypernatremia based on understanding of its pathophysiology.

  • ▪

    To provide an approach to the treatment of patients with hypernatremia based on whether the disorder is acute or chronic.

Case 11-1: Concentrate on the Danger

A 16-year-old young man who used to weigh 50 kg, had a craniopharyngioma resected. During surgery, his urine output was 3 L over 5 hours. His P Na rose from 140 to 150 mmol/L. During this time period, he received 3 L of isotonic saline. His urine osmolality (U Osm ) was 120 mosmol/kg H 2 O, and the sum of the concentrations of Na + ions and potassium (K + ) ions in his urine (U Na + U K ) was 50 mmol/L. Following the administration of desmopressin (dDAVP), his U Osm rose quickly to 375 mosmol/kg H 2 O, and his U Na was 175 mmol/L.

Questions

  • Why did hypernatremia develop (see margin note)?

  • What are the goals for therapy for his hypernatremia?

Note

Case 11-2: What Is “Partial” About Partial Central Diabetes Insipidus?

A 32-year-old healthy man had a recent basal skull fracture. Since his head injury, his urine output has been consistently ∼4 L/day and his U Osm is ∼200 mosmol/kg H 2 O in multiple 24-hour urine collections. In blood samples drawn early in the morning, his P Na was ∼143 mmol/L. Vasopressin was not detectable in his plasma from blood samples drawn at the same time. During the daytime, his U Osm was consistently ∼90 mosmol/kg H 2 O and his P Na was ∼137 mmol/L. When he was given dDAVP, his urine flow rate decreased to 0.5 mL/min and his U Osm rose to 900 mosm/kg H 2 O. When he stopped drinking water after supper, his sleep was not interrupted by a need to void. In fact, his U Osm was ∼425 mosmol/kg H 2 O in several first voided urine samples in the morning. Of interest, his urine flow rate fell to 0.5 mL/min and his U Osm rose to 900 mosmol/kg H 2 O after an infusion of hypertonic saline.

Questions

  • What is the basis for the high urine flow rate in this patient?

  • What are the options for therapy?

Case 11-3: Where Did the Water Go?

A 55-year-old obese man who weighs 80 kg has had type 2 diabetes mellitus for the last 15 years. In the past several months, he complained of feeling very thirsty after eating a large meal. This usually lasted for a few hours and then subsided. This time, however, 12 hours after a large meal, which contained much more NaCl than his usual intake, he continued to have an intense feeling of thirst, despite drinking a large volume of water. He denied passing a large volume of urine. On arrival at the emergency room, he was alert and responded appropriately to questions. His blood pressure was 150/90 mm Hg, his pulse rate was 96 beats per minute (usual values for him), his weight was 1 kg higher than usual, and his ECF volume appeared to be normal. Fundoscopic examination showed changes consistent with diabetic retinopathy; he also had signs of peripheral neuropathy on clinical examination. Laboratory findings from a venous blood sample drawn when he presented to the emergency room are shown in the following table. Similar values were noted on another blood sample obtained 2 hours later. His arterial blood pH was 7.40. His hematocrit was similar to values from previous laboratory results.

P Na mmol/L 169
P K mmol/L 5.2
P Glucose mg/dL 180
mmol/L 10
P Creatinine mg/dL 1.8
μmol/L 157
P Albumin g/dL 3.8
g/L 38
Hematocrit 0.36
P Cl mmol/L 133

P HCO 3 		mmol/L 25
BUN (P Urea) mg/dL 22
(mmol/L) (8)
Hemoglobin g/dL 12.5
g/L 125

Questions

  • What is the basis for the hypernatremia (in quantitative terms): a positive balance for Na + ions and/or a negative balance for water?

  • Why does he have such a severe degree of hypernatremia?

  • What is the therapy of hypernatremia in this patient?

Part A

Background

Synopsis of the Pertinent Physiology

Concentration of Sodium Ions in Plasma

The P Na reflects the ratio of the amount of Na + ions to the volume of water in the ECF compartment. The actual concentration of Na + ions in plasma water is 152 mmol/kg H 2 O. Measured per liter of plasma, however, the P Na is 140 mmol/L, because each liter of plasma has 6% to 7% nonaqueous volume (lipids and proteins). The normal range for the P Na is 136 to 145 mmol/L; thus, hypernatremia is defined as a P Na that is greater than 145 mmol/L.

Hypernatremia can be primarily caused by a negative balance for water or a positive balance for Na + ions ( Figure 11-1 ). Hypernatremia is associated with a decrease in ICF volume unless its basis is a shift of water into cells secondary to a gain of effective osmoles in the ICF compartment (e.g., because of seizures or rhabdomyolysis; see Figure 9-22 ). The ECF volume, on the other hand, may be increased (because of positive balance of Na + ions), normal, or decreased (because of a negative water balance, or because of a negative balance of both water and of Na + ions, but with a larger negative balance of water than that of Na + ions), depending on the basis for the rise in the P Na .

Figure 11-1, Cell Size During Hypernatremia.

Responses to Hypernatremia

When the P Na rises, the water control system elicits two responses that are designed to lower the P Na to prevent a further decrease in brain cell size: There is an input response (stimulation of thirst) and an output response (minimizing the loss of water in the urine).

The rise in the P Na is sensed in a group of cells in the hypothalamus (called the osmostat, or, better, the tonicity receptor). The main osmosensory cells appear to be located in the organum vasculosum laminae terminalis. In response to a high P Na , this tonicity receptor sends messages to the thirst center to stimulate water intake and to the posterior pituitary to release vasopressin ( Figure 11-2 ).

Figure 11-2, Water Control System.

Thirst

It is virtually impossible to have the P Na increase above the normal range if the thirst response is intact and water is available. In patients with a significant degree of hypernatremia, one must look for a reason why they cannot appreciate thirst or are unable to drink water. Examples include unconsciousness, disorders involving the osmostat or the thirst center (e.g., following a subarachnoid hemorrhage), inability to communicate the desire for water (e.g., infants, a patient with a stroke), inability to obtain water (e.g., inability to move), recurrent vomiting, or mechanical obstruction of the upper gastrointestinal tract (e.g., an esophageal tumor).

Renal response

A rise in P Na triggers the release of vasopressin, which makes the cortical and medullary collecting ducts permeable to water. This results in conservation of water with the excretion of a small volume of urine with the highest concentration of effective osmoles (discussed in the following).

Vasopressin is synthesized by the magnocellular neurons in the supraoptic and paraventricular nuclei of the hypothalamus and is transported down the axons of the supraoptical–hypophyseal tract to be stored in and released from the posterior pituitary (neurohypophysis). Binding of vasopressin to its V2 receptors (V2R) in the basolateral membrane of principal cells in the collecting ducts stimulates adenylyl cyclase to produce cyclic adenosine monophoshate (cAMP), which in turn activates protein kinase A (PKA). PKA phosphorylates aquaporin 2 (AQP2) water channels, which causes their shuttling from an intracellular store to the luminal membrane of principal cells.

When vasopressin acts, the urine flow rate is determined by the rate of excretion of effective osmoles and the effective (“nonurea”) osmolality in the inner medullary interstitial compartment. Because cells in the inner medullary collecting duct (MCD) have urea transporters (UTA-1 and UTA-3) in their luminal membranes when vasopressin acts, urea is usually an ineffective osmole (the concentration of urea is nearly equal on the two sides of that membrane), so urea does not obligate the excretion of water. Therefore, the effective osmoles in the urine are Na + and K + ions and their accompanying anions; thus, the excretion of effective osmoles in the urine is calculated as 2(U Na + U K ). On a typical Western diet, the rate of excretion of effective osmoles is typically 450 mosmol/day, and the effective osmolality in the inner medullary interstitial compartment is close to 600 mosmol/kg H 2 O. Hence, the minimum urine flow rate is close to 0.75 L/day or 0.5 mL/min. The urine flow rate is higher when the rate of excretion of effective osmoles rises.

The effective U Osm is virtually identical to the effective osmolalty in the inner medullary interstitial compartment when vasopressin acts. Notwithstanding, the effective osmolality in the inner medullary interstitial compartment can be lower because of several potential factors: diseases that cause medullary interstitial damage, drugs or disorders that compromise the function of the loop of Henle, or if the renal medulla is washed out by a prior water or osmotic diuresis.

If vasopressin is not present (e.g., in patients with central diabetes insipidus [DI]) or if it fails to act (e.g., in patients with congenital nephrogenic DI), the late distal nephron segments lack AQP2 in their luminal membrane and therefore are impermeable to water. In this setting, the urine flow rate is determined by the volume of filtrate that is delivered to the distal nephron minus the volume of water reabsorbed via residual water permeability in the inner MCD. The volume of filtrate delivered to the distal nephron is a function of the glomerular filtration rate and the volume of fluid reabsorbed in the proximal convoluted tubule (PCT; see Chapter 9 ). In the absence of vasopressin actions, the rate of excretion of osmoles influences the U Osm but not the urine flow rate.

Regulation of Brain Cell Volume

In response to chronic hypernatremia, cells in the brain gain effective osmoles. This begins with an influx of Na + and Cl − ions, which usually occurs via the furosemide-sensitive Na + , K + , 2 Cl − cotransporter-1 (NKCC-1), but it is also possible that this may be achieved by parallel flux through the Na + /H + cation exchanger and the Cl − /
HCO 3 − anion exchanger. The second mechanism for increasing the size of shrunken brain cells is via an increase in the number of organic compounds in brain cells (e.g., taurine and myoinositol), which seems to account for close to half of the increase in the number of effective osmoles in this adaptive process. As a result, water shifts from the ECF compartment into brain cells, which returns their volume toward normal ( Figure 11-3 ). Although it is estimated that it takes 48 hours to accumulate enough effective osmoles, it is uncertain as to when this adaptive response is complete. Hence, the time frame that separates acute from chronic hypernatremia is not known with certainty and may differ from patient to patient. It is important to appreciate this adaptive change because if the P Na were to fall rapidly, brain cells would swell, and this could cause a dangerous rise in the intracranial pressure.

Figure 11-3, Regulation of Brain Cell Volume During Hypernatremia.

Pathophysiology of Hypernatremia

Hypernatremia can be primarily caused by a negative balance for water or a positive balance for Na + ( Table 11-1 ). In some patients with hypernatremia, there is a deficit of both Na + ions and water, with a proportionately larger deficit of water than of Na + ions. For hypernatremia to develop, there must be a defect in sensing thirst, communicating the desire for water, and/or an inability to obtain water.

TABLE 11-1
Causes OF Hypernatremia
Primary Water Deficit
Reduced Water Intake for Many Days

  • Lack of water

  • Inability to gain access to, or to drink, water

  • Defective thirst caused by altered mental state, psychological disorder, or diseases involving the osmoreceptor and/or the thirst center

Increased Water Loss

  • Renal loss: central DI, release of a vasopressinase from a necrotic tissue, nephrogenic DI, osmotic diuresis

  • Gastrointestinal loss: vomiting, osmotic diarrhea

  • Cutaneous loss: excessive sweating

  • Respiratory loss: hyperventilation

Shift of Water into Cells

  • Gain of effective osmoles in the intracellular fluid compartment (e.g., because of seizures, rhabdomyolysis)

Primary Gain of Na + Ions

  • Administration of intravenous fluid with a higher concentration of Na + + K + ions than their concentration in the urine during an osmotic or a water diuresis

  • Infusion of hypertonic NaCl or NaHCO 3 in patients with oliguria

  • Ingestion of sea water or replacing sugar by NaCl in feeding formula in infants

DI , Diabetes insipidus.

Hypernatremia Caused by a Deficit of Water

Reduced water intake

Hypernatremia may develop if there is reduced water intake for several days, even if there is an appropriate renal response with decreased urine output. This is because a water deficit develops as loss of water through the skin and the respiratory tract continues (about 800 mL/day in an adult patient, more in a hot dry environment and with exercise). Hypernatremia may develop in a patient who has a lesion in the central nervous system involving the osmostat and/or the thirst center or a patient who is unable to obtain enough water. In addition to decreased mobility, decreased sensitivity to thirst may be present in elderly subjects. Breastfed infants are completely dependent on their mothers for the intake of water. They may develop hypernatremia if they do not receive a sufficient number of feeds or if there are problems with breastfeeding. Infants also are at risk of hypernatremia from nonrenal water loss (e.g., caused by vomiting). In addition, infants in their first month of life have a reduced capacity to decrease their urine volume, a physiologic form of nephrogenic DI (see Part D for more discussion).

Water loss

Water loss is the most frequent cause of hypernatremia; the sites of water loss are discussed below.

Nonrenal water loss

Sweat

Sweat is important for thermoregulation because the evaporation of 1 L of water causes the loss of 500 to 600 kcal (heat of evaporation). Sweat is a hypotonic solution with a concentration of Na + ions that is close to 20 to 30 mmol/L. Because this water loss is derived from total body water rather than solely from the ECF compartment, and because the concentration of Na + ions in sweat is low, an appreciable degree of effective arterial blood volume (EABV) contraction does not usually develop because of excessive sweating. The usual volume of sweat is close to 0.5 L/day in an adult. Losses in sweat increase in febrile patients and can rise to 2 L per hour during exercise in a hot environment.

Respiratory tract

Because inspired air is not fully saturated with water, it gets humidified in the alveoli at normal body temperature. The source of this water, however, is from the oxidation of fuels (i.e., metabolic water). In more detail, oxidation of food yields H 2 O and CO 2 in a 1:1 proportion. Because the partial pressures of H 2 O and CO 2 in alveolar air are similar (47 and 40 mm Hg), H 2 O and CO 2 are also lost in almost a 1:1 proportion. Hence, there is no appreciable decrease in total body water as a result of loss of water in the alveolar air, unless the patient is hyperventilating ( Figure 11-4 ).

Figure 11-4, Fate of Metabolic Water.

Evaporation of water in the upper respiratory tract, however, results in loss of body water. The volume of this water loss is larger when the rate of ventilation is high.

Gastrointestinal tract

The loss of gastric secretions containing HCl is a loss of a hypotonic solution because at a pH of 1, the concentration of Cl − ions in gastric secretions is 100 mmol/L, and for every Cl − ion lost, one new
HCO 3 − ion is added to the body (see Figure 7-1 ). Loss of fluid containing both gastric and small intestinal secretions is also a loss of hypotonic solution. This is because if, for example, 1 L of isotonic HCl from gastric fluid were to react with 1 L of isotonic NaHCO 3 from the fluid secreted in the small intestine, the resulting solution will have 150 mmol of Na + ions and 150 mmol of Cl − ions in a total volume of 2 L. Therefore, the loss of this solution results in the loss of 2 L of half-isotonic NaCl.

Hypotonic fluid can be lost in osmotic diarrhea but not in secretory diarrhea. In osmotic diarrhea, the fluid lost is hypotonic to plasma because it contains organic osmoles (e.g., lactulose), and hence has a lower concentration of Na + ions.

Renal water loss

Renal water loss could be caused by a water diuresis (DI), an osmotic diuresis, or a renal concentrating defect (see Chapter 12 for more details).

DI could be caused by a lesion in the hypothalamic–posterior pituitary axis, which controls the production and release of vasopressin (central DI), the presence of a circulating vasopressinase that breaks down vasopressin, or a renal lesion that prevents the binding of vasopressin to its V2R or interferes with signaling to cause the insertion of AQP2 in the luminal membrane of principal cells in distal nephron (nephrogenic DI; see margin note).

In a patient with glucose- or urea-induced osmotic diuresis (see Chapter 12 ), the urine is hypotonic with a concentration of Na + + K + ions of typically 50 mmol/L. Hence, a water deficit and hypernatremia may develop.

Water loss could also be because of a renal concentrating defect. A low medullary interstitial effective osmolality could be because of diseases that cause medullary interstitial damage or because of drugs or disorders that compromise the function of the loop of Henle.

Classification of Nephrogenic DI

  • We use the term nephrogenic DI to describe only the group of disorders in which there is diminished effectiveness of vasopressin to cause the insertion of AQP2 in the luminal membrane of principal cells in the distal nephron.

  • We do not use the term nephrogenic DI to indicate a disorder in which there is a lesion that leads to a lower medullary interstitial osmolality, because from a pathophysiologic perspective, it is a different disorder. We prefer to use the term “renal concentrating defect” to describe this disorder.

Shift of water

In a setting where there is an acute rise in the number of effective osmoles in skeletal muscle cells (e.g., seizures, rhabdomyolysis), the hydrolysis of phosphocreatine to inorganic divalent phosphate and creatine can raise the number of effective osmoles in these cells. An acute shift of a large volume of water from the ECF compartment into muscle cells may occur for two reasons: the large size of that organ and its very high content of phosphocreatine (∼25 mmol/kg). If L-lactic acid is produced in muscle cells during a seizure and the H + ions are titrated by intracellular proteins, accumulation of L-lactate anions increases the number of effective osmoles in muscle cells (see Discussion of Case 9-1 ).

An acute shift of water into the lumen of the intestinal tract may also occur, causing hypernatremia. To shift water into the lumen of the small intestine, there must be an accumulation of a large number of osmoles from the digestion of food because of a slow GI transit time or obstruction of the intestinal tract. An example of this pathophysiology is illustrated in Case 11-3 .

Hypernatremia Caused by Na + Ion Gain

Hypernatremia caused by a gain of Na + ions rarely occurs in an outpatient setting (e.g., ingestion of sea water, replacing sugar with salt in preparation of pediatric feeding formula, inducing abortion with hypertonic saline, suicide attempts). In contrast, hypernatremia because of a gain of Na + ions commonly occurs in a hospital setting as a result of the administration of a hypertonic Na + ion salt intravenously (e.g., NaHCO 3 to treat a cardiac arrest) or when hypotonic Na + ion losses are replaced with isotonic saline infusion (e.g., during the treatment of a patient with DI, or an osmotic diuresis caused by organic solutes such as glucose or urea).

Part B

Clinical Approach

Tools in the Clinical Approach to the Patient With Hypernatremia

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here

Related Posts