Hyponatremia is one of the most common electrolyte abnormalities encountered in clinical practice. The frequency of the disorder varies according to definition and clinical setting but has been reported to be present in 28% of patients upon hospital admission and in 7% of patients attending an ambulatory community clinic.1 Increasing age, medications, various disease states, and administration of hypotonic fluids are among the known risk factors for the disorder.

The mortality rate in hyponatremic patients is approximately 3 times that of normonatremic hospitalized patients.25 Outcomes are particularly poor in those patients whose serum sodium (Na⁺) falls during a hospitalization. In 1 prospective study the mortality rate in patients with a normal serum Na⁺ concentration was 0.2% in comparison to a mortality rate of 11.2% and 25% in patients with a serum Na⁺ concentration 130 mEq/L and 120 mEq/L, respectively.2 In a recent retrospective cohort study of 10,899 hospitalized patients, the incidence of hyponatremia (135 mmol/L) at admission was 5.5%.5 As compared to those with normonatremia, these patients were more likely to require intensive care and mechanical ventilation within 48 hours of hospitalization. In addition, hospital mortality, mean length of stay, and costs were significantly greater among patients with hyponatremia than those without.

The association with hyponatremia and adverse outcomes could be the direct result of hyponatremia, the comormidities that lead to the electrolyte derangement, or both. Whatever the mechanism, hyponatremia should not be viewed as an innocuous condition. Rather, clinicians should view this disorder with urgency and institute measures to prevent any further decline in the serum Na⁺ concentration and initiate appropriate therapy for its correction. This review will first briefly summarize the pathogenesis of hyponatremia and then discuss various disease states encountered in the hospital setting in which hyponatremia is frequently present.

Pathogenesis of Hyponatremia

Hyponatremia is generally associated with a hypoosmolar state and is a marker for a disturbance in water balance. Stated differently, all hyponatremia is dilutional. The approach to the patient with hyponatremia is outlined in Figure 1.

Figure 1

Is the Hyponatremia Representative of a Hypoosmolar State?

There are 3 causes of hyponatremia in which it is not associated with a hypoosmolar state. The first of these is pseudohyponatremia which involves an abnormal measurement of the serum Na⁺. This occurs in patients with hyperglobulinemia or hypertriglyceridemia in whom plasma water relative to plasma solids is decreased in blood, leading to less Na⁺ in a given volume of blood. In general, this problem is becoming less prevalent as many laboratories are using Na⁺ electrodes without diluting the blood such that the Na⁺ measurement becomes independent of plasma water and nonaqueous contents.

A second cause of hyponatremia in the absence of a hypoosmolar state involves true hyponatremia but with elevations in the concentration of another osmole. Clinical examples include hyperglycemia as seen in uncontrolled diabetes or rarely hypertonic infusion of mannitol used in the treatment of cerebral edema. The accumulation of these effective osmoles creates an osmotic force causing water to move from the intracellular to the extracellular space thus diluting the serum Na⁺. For every 100 mg/dL rise in glucose or mannitol, the serum Na⁺ will quickly fall by 1.6 mEq/L. This increase in tonicity also stimulates thirst and arginine vasopressin (AVP) secretion, both of which contribute to further water retention. As a result the plasma osmolality and serum Na⁺ concentration will continue to fall. Once the plasma osmolality normalizes the serum Na⁺ will have decreased by 2.8 mEq/L for every 100 mg/dL rise in glucose.

The third cause of hyponatremia in the absence of a hypoosmolar state is the addition of an isosmotic (or near isosmotic) non‐Na⁺ containing fluid to the extracellular space. This situation typically occurs during a transurethral resection of the prostate or during laprascopic surgery when large amounts of a nonconducting flushing solution containing glycine or sorbitol are absorbed systemically.

Is the Kidney's Ability to Dilute the Urine Intact?

The presence of hypotonic hyponatremia implies that water intake exceeds the ability of the kidney to excrete water. In unusual circumstances, this can occur when the kidneys ability to excrete free water is intact. However, because a normal kidney can excrete 18 L of water per day, the presence of hyponatremia with normal renal water excretion implies the patient is drinking >20 L water/day. This condition is referred to as primary polydipsia. These patients should have a urine osmolality 100 mOsm/L. While primary polydipsia is a common condition which leads to polyuria and polydipsia, it is uncommon as a sole cause of hyponatremia.

Hyponatremia in association with a maximally dilute urine can also result from more moderate fluid intake combined with extremely limited solute intake, a condition often referred to as beer potomania syndrome. In normal subjects, daily solute excretion is usually in the range of 800 mOsm to 1000 mOsm per day. Since the limit of urinary dilution is approximately 50 mOsm/L, then maximum urine output can be calculated to be approximately 16 L to 20 L per day (1000 mOsm/L/50 mOsm/L = 20). Individuals who drink beer or who are ingesting a fad diet have very limited protein intake so that daily solute excretion may be as low as 200 mOsm per day. In this setting, water intake >4 L/day (200 mOsm/50 mOsm/L = 4 L) will exceed renal water excretion and cause hyponatremia. Urine osmolality will be maximally dilute in such a patient.

In the absence of primary polydipsia, hyponatremia is associated with decreased renal water excretion and a urine that is inappropriately concentrated. It is important to note that in the presence of hyponatremia urine should be maximally dilute and a urine osmolality higher than this (>100 mOsm/L) is inappropriate. An inappropriately concentrated urine implies a defect in renal water excretion.

Excretion of water by the kidney is dependent on three factors. First, there must be adequate delivery of filtrate to the tip of the loop of Henle. Second, solute absorption in the ascending limb and the distal nephron must be normal so that the tubular fluid will be diluted. Lastly, AVP levels must be low in the plasma. Of these 3 requirements for water excretion, the one which is probably most important in the genesis of hyponatremia is the failure to maximally suppress AVP levels. In many conditions, decreased delivery of filtrate to the tip of the loop of Henle also contributes.

What is the Volume Status of the Patient?

In patients with hypotonic hyponatremia with an inappropriately concentrated urine, one needs to define whether effective arterial volume is decreased. Most causes of hyponatremia result from a decrease in effective arterial volume which leads to both baroreceptor‐mediated stimulation of AVP secretion and decreased distal delivery of filtrate to the tip of the loop of Henle. If effective arterial volume is low, extracellular fluid (ECF) volume can be low in the volume‐depleted patient (hypovolemic hyponatremia) or can be high in the edematous patient (hypervolemic hyponatremia). If effective arterial volume is normal, one is dealing with the euvolemic causes of hyponatremia (isovolemic hyponatremia).

The clinical determination of effective arterial volume is usually straightforward. On physical examination the best index of effective arterial volume is the presence or absence of an orthostatic change in pulse and blood pressure. Urinary electrolytes are also extremely useful in the assessment of effective arterial volume. Patients with a low effective arterial volume will tend to have a low urinary Na⁺ and Cl concentration and low fractional excretions of Na⁺ and Cl in the urine. Patients with euvolemic hyponatremia will be in balance and will excrete Na⁺ and Cl at rates that reflect dietary intake of Na⁺ and Cl. Generally urinary Na⁺ and Cl is >20 mEq/L and fractional excretions of these electrolytes are >1%.

Plasma composition can also be used to assess effective arterial volume. The blood urea nitrogen (BUN) is particularly sensitive to effective arterial volume. In patients with a normal serum creatinine concentration, a high BUN suggests a low effective arterial volume and a low BUN suggests a high effective arterial volume. The plasma uric acid can also be used as a sensitive index of effective arterial volume. In comparing patients with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and other causes of hyponatremia, patients with low effective arterial volume tend to have an elevated serum uric acid. The serum urate is low in patients with SIADH. This is due to the fact that these patients are volume expanded although it is clinically difficult to detect the degree of volume expansion.

Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)

In patients who are determined to be clinically euvolemic, a concentrated urine and high AVP levels are inappropriate. The most common cause of this condition is SIADH. This syndrome is generally associated with diseases of the central nervous system, pulmonary diseases, and neoplasms. These conditions lead to secretion of AVP which is inappropriate both from the standpoint of plasma osmolality and effective arterial volume. A number of other etiologies cause a condition of hypoosmolality associated with euvolemia and can mimic the syndrome of inappropriate AVP secretion. These include isolated glucocorticoid deficiency (normal mineralocorticoid activity), hypothyroidism, pain, nausea, acute psychosis, and a variety of drugs.

Clinical Conditions Associated With Hyponatremia in the Hospital Setting

Treatment of Hyponatremia

Symptoms of hyponatremia include nausea and malaise, which can be followed by headache, lethargy, muscle cramps, disorientation, restlessness and obtundation, and seizures. The principal danger of hyponatremia or hypernatremia relates to effects on central nervous system function due to changes in brain size (Figure 2).

Figure 2

Hyponatremia initially leads to cell swelling driven by the higher intracellular osmolality. The net result is equilibration of intracellular and extracellular osmolality at the expense of increased brain volume. Cells in general, and brain cells in particular, then respond by decreasing the number of intracellular osmoles and as intracellular osmolality decreases, cell size returns toward normal despite the presence of hyponatremia. If the decrease in ECF osmolality is slow, there will be no measurable cell swelling. This pathophysiologic sequence correlates well with clinical observations. If hyponatremia is slow in onset, neurologic symptoms and permanent brain damage are unusual, even if the decreases in Na⁺ concentration and ECF osmolality are large. Conversely, if hyponatremia is rapid in onset, cerebral edema and significant CNS symptoms and signs can occur with lesser changes in serum Na⁺ concentration.

When treating a patient with hyponatremia, the Na⁺ concentration should be raised at the rate at which it fell. In a patient whose serum Na⁺ concentration has decreased rapidly (48 hours), neurologic symptoms are frequently present and there is cerebral edema. In this setting there has not been sufficient time to remove osmoles from the brain and rapid return to normal ECF osmolality merely returns brain size to normal. In general, the development of hyponatremia in the outpatient setting is more commonly chronic in duration and should be corrected slowly. By contrast, hyponatremia of short duration is more likely to be encountered in hospitalized patients receiving intravenous free water. Use of ecstasy, exercise‐induced hyponatremia, or patients with primary polydipsia can also develop acute hyponatremia and if symptomatic may similarly require rapid correction. Raising the serum Na⁺ concentration by 4 mEq/L to 6 mEq/L over a several hour period is both safe and effective in preventing untoward effects of acute hyponatremia.22 A reasonable strategy to accomplish this goal is the regimen recommended for the treatment of athletes with hyponatremia and encephalopathy.23 These guidelines suggest an immediate bolus of 100 mL 3% NaCl (513 mEq/L). If there is no neurologic improvement two additional 100 mL 3% NaCl bolus infusions separated by 10 minute intervals can be given.

In patients with chronic hyponatremia (>48 hours duration) the serum Na⁺ concentration has fallen slowly. Neurologic symptoms are generally minimal, brain size is normal, and the number of intracellular osmoles is decreased. Sudden return of ECF osmolality to normal values will lead to cell shrinkage and possibly precipitate osmotic demyelination. Experts in the field suggest this complication can be prevented by adhering to the following limits of correction: 10 mmol/L in 24 hours, 18 mmol/L in 48 hours, and 20 mmol/L in 72 hours.22 In order to maximize patient safety, the goals of therapy should be more modest: 6 to 8 mmol/L in 24 hours, 12 to 14 mmol/L in 48 hours, and 14 to 16 mmol/L in 72 hours.

A formula designed to predict the increase in serum Na⁺ concentration to be expected from the infusion of 1 L of a given infusion is given below: 1

Hyponatremia is one of the most common electrolyte abnormalities encountered in clinical practice. The frequency of the disorder varies according to definition and clinical setting but has been reported to be present in 28% of patients upon hospital admission and in 7% of patients attending an ambulatory community clinic.1 Increasing age, medications, various disease states, and administration of hypotonic fluids are among the known risk factors for the disorder.

The mortality rate in hyponatremic patients is approximately 3 times that of normonatremic hospitalized patients.25 Outcomes are particularly poor in those patients whose serum sodium (Na⁺) falls during a hospitalization. In 1 prospective study the mortality rate in patients with a normal serum Na⁺ concentration was 0.2% in comparison to a mortality rate of 11.2% and 25% in patients with a serum Na⁺ concentration 130 mEq/L and 120 mEq/L, respectively.2 In a recent retrospective cohort study of 10,899 hospitalized patients, the incidence of hyponatremia (135 mmol/L) at admission was 5.5%.5 As compared to those with normonatremia, these patients were more likely to require intensive care and mechanical ventilation within 48 hours of hospitalization. In addition, hospital mortality, mean length of stay, and costs were significantly greater among patients with hyponatremia than those without.

The association with hyponatremia and adverse outcomes could be the direct result of hyponatremia, the comormidities that lead to the electrolyte derangement, or both. Whatever the mechanism, hyponatremia should not be viewed as an innocuous condition. Rather, clinicians should view this disorder with urgency and institute measures to prevent any further decline in the serum Na⁺ concentration and initiate appropriate therapy for its correction. This review will first briefly summarize the pathogenesis of hyponatremia and then discuss various disease states encountered in the hospital setting in which hyponatremia is frequently present.

Pathogenesis of Hyponatremia

Hyponatremia is generally associated with a hypoosmolar state and is a marker for a disturbance in water balance. Stated differently, all hyponatremia is dilutional. The approach to the patient with hyponatremia is outlined in Figure 1.

Figure 1

Is the Hyponatremia Representative of a Hypoosmolar State?

There are 3 causes of hyponatremia in which it is not associated with a hypoosmolar state. The first of these is pseudohyponatremia which involves an abnormal measurement of the serum Na⁺. This occurs in patients with hyperglobulinemia or hypertriglyceridemia in whom plasma water relative to plasma solids is decreased in blood, leading to less Na⁺ in a given volume of blood. In general, this problem is becoming less prevalent as many laboratories are using Na⁺ electrodes without diluting the blood such that the Na⁺ measurement becomes independent of plasma water and nonaqueous contents.

A second cause of hyponatremia in the absence of a hypoosmolar state involves true hyponatremia but with elevations in the concentration of another osmole. Clinical examples include hyperglycemia as seen in uncontrolled diabetes or rarely hypertonic infusion of mannitol used in the treatment of cerebral edema. The accumulation of these effective osmoles creates an osmotic force causing water to move from the intracellular to the extracellular space thus diluting the serum Na⁺. For every 100 mg/dL rise in glucose or mannitol, the serum Na⁺ will quickly fall by 1.6 mEq/L. This increase in tonicity also stimulates thirst and arginine vasopressin (AVP) secretion, both of which contribute to further water retention. As a result the plasma osmolality and serum Na⁺ concentration will continue to fall. Once the plasma osmolality normalizes the serum Na⁺ will have decreased by 2.8 mEq/L for every 100 mg/dL rise in glucose.

The third cause of hyponatremia in the absence of a hypoosmolar state is the addition of an isosmotic (or near isosmotic) non‐Na⁺ containing fluid to the extracellular space. This situation typically occurs during a transurethral resection of the prostate or during laprascopic surgery when large amounts of a nonconducting flushing solution containing glycine or sorbitol are absorbed systemically.

Is the Kidney's Ability to Dilute the Urine Intact?

The presence of hypotonic hyponatremia implies that water intake exceeds the ability of the kidney to excrete water. In unusual circumstances, this can occur when the kidneys ability to excrete free water is intact. However, because a normal kidney can excrete 18 L of water per day, the presence of hyponatremia with normal renal water excretion implies the patient is drinking >20 L water/day. This condition is referred to as primary polydipsia. These patients should have a urine osmolality 100 mOsm/L. While primary polydipsia is a common condition which leads to polyuria and polydipsia, it is uncommon as a sole cause of hyponatremia.

Hyponatremia in association with a maximally dilute urine can also result from more moderate fluid intake combined with extremely limited solute intake, a condition often referred to as beer potomania syndrome. In normal subjects, daily solute excretion is usually in the range of 800 mOsm to 1000 mOsm per day. Since the limit of urinary dilution is approximately 50 mOsm/L, then maximum urine output can be calculated to be approximately 16 L to 20 L per day (1000 mOsm/L/50 mOsm/L = 20). Individuals who drink beer or who are ingesting a fad diet have very limited protein intake so that daily solute excretion may be as low as 200 mOsm per day. In this setting, water intake >4 L/day (200 mOsm/50 mOsm/L = 4 L) will exceed renal water excretion and cause hyponatremia. Urine osmolality will be maximally dilute in such a patient.

In the absence of primary polydipsia, hyponatremia is associated with decreased renal water excretion and a urine that is inappropriately concentrated. It is important to note that in the presence of hyponatremia urine should be maximally dilute and a urine osmolality higher than this (>100 mOsm/L) is inappropriate. An inappropriately concentrated urine implies a defect in renal water excretion.

Excretion of water by the kidney is dependent on three factors. First, there must be adequate delivery of filtrate to the tip of the loop of Henle. Second, solute absorption in the ascending limb and the distal nephron must be normal so that the tubular fluid will be diluted. Lastly, AVP levels must be low in the plasma. Of these 3 requirements for water excretion, the one which is probably most important in the genesis of hyponatremia is the failure to maximally suppress AVP levels. In many conditions, decreased delivery of filtrate to the tip of the loop of Henle also contributes.

What is the Volume Status of the Patient?

In patients with hypotonic hyponatremia with an inappropriately concentrated urine, one needs to define whether effective arterial volume is decreased. Most causes of hyponatremia result from a decrease in effective arterial volume which leads to both baroreceptor‐mediated stimulation of AVP secretion and decreased distal delivery of filtrate to the tip of the loop of Henle. If effective arterial volume is low, extracellular fluid (ECF) volume can be low in the volume‐depleted patient (hypovolemic hyponatremia) or can be high in the edematous patient (hypervolemic hyponatremia). If effective arterial volume is normal, one is dealing with the euvolemic causes of hyponatremia (isovolemic hyponatremia).

The clinical determination of effective arterial volume is usually straightforward. On physical examination the best index of effective arterial volume is the presence or absence of an orthostatic change in pulse and blood pressure. Urinary electrolytes are also extremely useful in the assessment of effective arterial volume. Patients with a low effective arterial volume will tend to have a low urinary Na⁺ and Cl concentration and low fractional excretions of Na⁺ and Cl in the urine. Patients with euvolemic hyponatremia will be in balance and will excrete Na⁺ and Cl at rates that reflect dietary intake of Na⁺ and Cl. Generally urinary Na⁺ and Cl is >20 mEq/L and fractional excretions of these electrolytes are >1%.

Plasma composition can also be used to assess effective arterial volume. The blood urea nitrogen (BUN) is particularly sensitive to effective arterial volume. In patients with a normal serum creatinine concentration, a high BUN suggests a low effective arterial volume and a low BUN suggests a high effective arterial volume. The plasma uric acid can also be used as a sensitive index of effective arterial volume. In comparing patients with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and other causes of hyponatremia, patients with low effective arterial volume tend to have an elevated serum uric acid. The serum urate is low in patients with SIADH. This is due to the fact that these patients are volume expanded although it is clinically difficult to detect the degree of volume expansion.

Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)

In patients who are determined to be clinically euvolemic, a concentrated urine and high AVP levels are inappropriate. The most common cause of this condition is SIADH. This syndrome is generally associated with diseases of the central nervous system, pulmonary diseases, and neoplasms. These conditions lead to secretion of AVP which is inappropriate both from the standpoint of plasma osmolality and effective arterial volume. A number of other etiologies cause a condition of hypoosmolality associated with euvolemia and can mimic the syndrome of inappropriate AVP secretion. These include isolated glucocorticoid deficiency (normal mineralocorticoid activity), hypothyroidism, pain, nausea, acute psychosis, and a variety of drugs.

Clinical Conditions Associated With Hyponatremia in the Hospital Setting

Treatment of Hyponatremia

Symptoms of hyponatremia include nausea and malaise, which can be followed by headache, lethargy, muscle cramps, disorientation, restlessness and obtundation, and seizures. The principal danger of hyponatremia or hypernatremia relates to effects on central nervous system function due to changes in brain size (Figure 2).

Figure 2

Hyponatremia initially leads to cell swelling driven by the higher intracellular osmolality. The net result is equilibration of intracellular and extracellular osmolality at the expense of increased brain volume. Cells in general, and brain cells in particular, then respond by decreasing the number of intracellular osmoles and as intracellular osmolality decreases, cell size returns toward normal despite the presence of hyponatremia. If the decrease in ECF osmolality is slow, there will be no measurable cell swelling. This pathophysiologic sequence correlates well with clinical observations. If hyponatremia is slow in onset, neurologic symptoms and permanent brain damage are unusual, even if the decreases in Na⁺ concentration and ECF osmolality are large. Conversely, if hyponatremia is rapid in onset, cerebral edema and significant CNS symptoms and signs can occur with lesser changes in serum Na⁺ concentration.

When treating a patient with hyponatremia, the Na⁺ concentration should be raised at the rate at which it fell. In a patient whose serum Na⁺ concentration has decreased rapidly (48 hours), neurologic symptoms are frequently present and there is cerebral edema. In this setting there has not been sufficient time to remove osmoles from the brain and rapid return to normal ECF osmolality merely returns brain size to normal. In general, the development of hyponatremia in the outpatient setting is more commonly chronic in duration and should be corrected slowly. By contrast, hyponatremia of short duration is more likely to be encountered in hospitalized patients receiving intravenous free water. Use of ecstasy, exercise‐induced hyponatremia, or patients with primary polydipsia can also develop acute hyponatremia and if symptomatic may similarly require rapid correction. Raising the serum Na⁺ concentration by 4 mEq/L to 6 mEq/L over a several hour period is both safe and effective in preventing untoward effects of acute hyponatremia.22 A reasonable strategy to accomplish this goal is the regimen recommended for the treatment of athletes with hyponatremia and encephalopathy.23 These guidelines suggest an immediate bolus of 100 mL 3% NaCl (513 mEq/L). If there is no neurologic improvement two additional 100 mL 3% NaCl bolus infusions separated by 10 minute intervals can be given.

In patients with chronic hyponatremia (>48 hours duration) the serum Na⁺ concentration has fallen slowly. Neurologic symptoms are generally minimal, brain size is normal, and the number of intracellular osmoles is decreased. Sudden return of ECF osmolality to normal values will lead to cell shrinkage and possibly precipitate osmotic demyelination. Experts in the field suggest this complication can be prevented by adhering to the following limits of correction: 10 mmol/L in 24 hours, 18 mmol/L in 48 hours, and 20 mmol/L in 72 hours.22 In order to maximize patient safety, the goals of therapy should be more modest: 6 to 8 mmol/L in 24 hours, 12 to 14 mmol/L in 48 hours, and 14 to 16 mmol/L in 72 hours.

A formula designed to predict the increase in serum Na⁺ concentration to be expected from the infusion of 1 L of a given infusion is given below: 1

Hyponatremia is one of the most common electrolyte abnormalities encountered in clinical practice. The frequency of the disorder varies according to definition and clinical setting but has been reported to be present in 28% of patients upon hospital admission and in 7% of patients attending an ambulatory community clinic.1 Increasing age, medications, various disease states, and administration of hypotonic fluids are among the known risk factors for the disorder.

The mortality rate in hyponatremic patients is approximately 3 times that of normonatremic hospitalized patients.25 Outcomes are particularly poor in those patients whose serum sodium (Na⁺) falls during a hospitalization. In 1 prospective study the mortality rate in patients with a normal serum Na⁺ concentration was 0.2% in comparison to a mortality rate of 11.2% and 25% in patients with a serum Na⁺ concentration 130 mEq/L and 120 mEq/L, respectively.2 In a recent retrospective cohort study of 10,899 hospitalized patients, the incidence of hyponatremia (135 mmol/L) at admission was 5.5%.5 As compared to those with normonatremia, these patients were more likely to require intensive care and mechanical ventilation within 48 hours of hospitalization. In addition, hospital mortality, mean length of stay, and costs were significantly greater among patients with hyponatremia than those without.

The association with hyponatremia and adverse outcomes could be the direct result of hyponatremia, the comormidities that lead to the electrolyte derangement, or both. Whatever the mechanism, hyponatremia should not be viewed as an innocuous condition. Rather, clinicians should view this disorder with urgency and institute measures to prevent any further decline in the serum Na⁺ concentration and initiate appropriate therapy for its correction. This review will first briefly summarize the pathogenesis of hyponatremia and then discuss various disease states encountered in the hospital setting in which hyponatremia is frequently present.

Pathogenesis of Hyponatremia

Hyponatremia is generally associated with a hypoosmolar state and is a marker for a disturbance in water balance. Stated differently, all hyponatremia is dilutional. The approach to the patient with hyponatremia is outlined in Figure 1.

Figure 1

Is the Hyponatremia Representative of a Hypoosmolar State?

There are 3 causes of hyponatremia in which it is not associated with a hypoosmolar state. The first of these is pseudohyponatremia which involves an abnormal measurement of the serum Na⁺. This occurs in patients with hyperglobulinemia or hypertriglyceridemia in whom plasma water relative to plasma solids is decreased in blood, leading to less Na⁺ in a given volume of blood. In general, this problem is becoming less prevalent as many laboratories are using Na⁺ electrodes without diluting the blood such that the Na⁺ measurement becomes independent of plasma water and nonaqueous contents.

A second cause of hyponatremia in the absence of a hypoosmolar state involves true hyponatremia but with elevations in the concentration of another osmole. Clinical examples include hyperglycemia as seen in uncontrolled diabetes or rarely hypertonic infusion of mannitol used in the treatment of cerebral edema. The accumulation of these effective osmoles creates an osmotic force causing water to move from the intracellular to the extracellular space thus diluting the serum Na⁺. For every 100 mg/dL rise in glucose or mannitol, the serum Na⁺ will quickly fall by 1.6 mEq/L. This increase in tonicity also stimulates thirst and arginine vasopressin (AVP) secretion, both of which contribute to further water retention. As a result the plasma osmolality and serum Na⁺ concentration will continue to fall. Once the plasma osmolality normalizes the serum Na⁺ will have decreased by 2.8 mEq/L for every 100 mg/dL rise in glucose.

The third cause of hyponatremia in the absence of a hypoosmolar state is the addition of an isosmotic (or near isosmotic) non‐Na⁺ containing fluid to the extracellular space. This situation typically occurs during a transurethral resection of the prostate or during laprascopic surgery when large amounts of a nonconducting flushing solution containing glycine or sorbitol are absorbed systemically.

Is the Kidney's Ability to Dilute the Urine Intact?

The presence of hypotonic hyponatremia implies that water intake exceeds the ability of the kidney to excrete water. In unusual circumstances, this can occur when the kidneys ability to excrete free water is intact. However, because a normal kidney can excrete 18 L of water per day, the presence of hyponatremia with normal renal water excretion implies the patient is drinking >20 L water/day. This condition is referred to as primary polydipsia. These patients should have a urine osmolality 100 mOsm/L. While primary polydipsia is a common condition which leads to polyuria and polydipsia, it is uncommon as a sole cause of hyponatremia.

Hyponatremia in association with a maximally dilute urine can also result from more moderate fluid intake combined with extremely limited solute intake, a condition often referred to as beer potomania syndrome. In normal subjects, daily solute excretion is usually in the range of 800 mOsm to 1000 mOsm per day. Since the limit of urinary dilution is approximately 50 mOsm/L, then maximum urine output can be calculated to be approximately 16 L to 20 L per day (1000 mOsm/L/50 mOsm/L = 20). Individuals who drink beer or who are ingesting a fad diet have very limited protein intake so that daily solute excretion may be as low as 200 mOsm per day. In this setting, water intake >4 L/day (200 mOsm/50 mOsm/L = 4 L) will exceed renal water excretion and cause hyponatremia. Urine osmolality will be maximally dilute in such a patient.

In the absence of primary polydipsia, hyponatremia is associated with decreased renal water excretion and a urine that is inappropriately concentrated. It is important to note that in the presence of hyponatremia urine should be maximally dilute and a urine osmolality higher than this (>100 mOsm/L) is inappropriate. An inappropriately concentrated urine implies a defect in renal water excretion.

Excretion of water by the kidney is dependent on three factors. First, there must be adequate delivery of filtrate to the tip of the loop of Henle. Second, solute absorption in the ascending limb and the distal nephron must be normal so that the tubular fluid will be diluted. Lastly, AVP levels must be low in the plasma. Of these 3 requirements for water excretion, the one which is probably most important in the genesis of hyponatremia is the failure to maximally suppress AVP levels. In many conditions, decreased delivery of filtrate to the tip of the loop of Henle also contributes.

What is the Volume Status of the Patient?

In patients with hypotonic hyponatremia with an inappropriately concentrated urine, one needs to define whether effective arterial volume is decreased. Most causes of hyponatremia result from a decrease in effective arterial volume which leads to both baroreceptor‐mediated stimulation of AVP secretion and decreased distal delivery of filtrate to the tip of the loop of Henle. If effective arterial volume is low, extracellular fluid (ECF) volume can be low in the volume‐depleted patient (hypovolemic hyponatremia) or can be high in the edematous patient (hypervolemic hyponatremia). If effective arterial volume is normal, one is dealing with the euvolemic causes of hyponatremia (isovolemic hyponatremia).

The clinical determination of effective arterial volume is usually straightforward. On physical examination the best index of effective arterial volume is the presence or absence of an orthostatic change in pulse and blood pressure. Urinary electrolytes are also extremely useful in the assessment of effective arterial volume. Patients with a low effective arterial volume will tend to have a low urinary Na⁺ and Cl concentration and low fractional excretions of Na⁺ and Cl in the urine. Patients with euvolemic hyponatremia will be in balance and will excrete Na⁺ and Cl at rates that reflect dietary intake of Na⁺ and Cl. Generally urinary Na⁺ and Cl is >20 mEq/L and fractional excretions of these electrolytes are >1%.

Plasma composition can also be used to assess effective arterial volume. The blood urea nitrogen (BUN) is particularly sensitive to effective arterial volume. In patients with a normal serum creatinine concentration, a high BUN suggests a low effective arterial volume and a low BUN suggests a high effective arterial volume. The plasma uric acid can also be used as a sensitive index of effective arterial volume. In comparing patients with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and other causes of hyponatremia, patients with low effective arterial volume tend to have an elevated serum uric acid. The serum urate is low in patients with SIADH. This is due to the fact that these patients are volume expanded although it is clinically difficult to detect the degree of volume expansion.

Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)

In patients who are determined to be clinically euvolemic, a concentrated urine and high AVP levels are inappropriate. The most common cause of this condition is SIADH. This syndrome is generally associated with diseases of the central nervous system, pulmonary diseases, and neoplasms. These conditions lead to secretion of AVP which is inappropriate both from the standpoint of plasma osmolality and effective arterial volume. A number of other etiologies cause a condition of hypoosmolality associated with euvolemia and can mimic the syndrome of inappropriate AVP secretion. These include isolated glucocorticoid deficiency (normal mineralocorticoid activity), hypothyroidism, pain, nausea, acute psychosis, and a variety of drugs.

Clinical Conditions Associated With Hyponatremia in the Hospital Setting

Treatment of Hyponatremia

Symptoms of hyponatremia include nausea and malaise, which can be followed by headache, lethargy, muscle cramps, disorientation, restlessness and obtundation, and seizures. The principal danger of hyponatremia or hypernatremia relates to effects on central nervous system function due to changes in brain size (Figure 2).

Figure 2

Hyponatremia initially leads to cell swelling driven by the higher intracellular osmolality. The net result is equilibration of intracellular and extracellular osmolality at the expense of increased brain volume. Cells in general, and brain cells in particular, then respond by decreasing the number of intracellular osmoles and as intracellular osmolality decreases, cell size returns toward normal despite the presence of hyponatremia. If the decrease in ECF osmolality is slow, there will be no measurable cell swelling. This pathophysiologic sequence correlates well with clinical observations. If hyponatremia is slow in onset, neurologic symptoms and permanent brain damage are unusual, even if the decreases in Na⁺ concentration and ECF osmolality are large. Conversely, if hyponatremia is rapid in onset, cerebral edema and significant CNS symptoms and signs can occur with lesser changes in serum Na⁺ concentration.

When treating a patient with hyponatremia, the Na⁺ concentration should be raised at the rate at which it fell. In a patient whose serum Na⁺ concentration has decreased rapidly (48 hours), neurologic symptoms are frequently present and there is cerebral edema. In this setting there has not been sufficient time to remove osmoles from the brain and rapid return to normal ECF osmolality merely returns brain size to normal. In general, the development of hyponatremia in the outpatient setting is more commonly chronic in duration and should be corrected slowly. By contrast, hyponatremia of short duration is more likely to be encountered in hospitalized patients receiving intravenous free water. Use of ecstasy, exercise‐induced hyponatremia, or patients with primary polydipsia can also develop acute hyponatremia and if symptomatic may similarly require rapid correction. Raising the serum Na⁺ concentration by 4 mEq/L to 6 mEq/L over a several hour period is both safe and effective in preventing untoward effects of acute hyponatremia.22 A reasonable strategy to accomplish this goal is the regimen recommended for the treatment of athletes with hyponatremia and encephalopathy.23 These guidelines suggest an immediate bolus of 100 mL 3% NaCl (513 mEq/L). If there is no neurologic improvement two additional 100 mL 3% NaCl bolus infusions separated by 10 minute intervals can be given.

In patients with chronic hyponatremia (>48 hours duration) the serum Na⁺ concentration has fallen slowly. Neurologic symptoms are generally minimal, brain size is normal, and the number of intracellular osmoles is decreased. Sudden return of ECF osmolality to normal values will lead to cell shrinkage and possibly precipitate osmotic demyelination. Experts in the field suggest this complication can be prevented by adhering to the following limits of correction: 10 mmol/L in 24 hours, 18 mmol/L in 48 hours, and 20 mmol/L in 72 hours.22 In order to maximize patient safety, the goals of therapy should be more modest: 6 to 8 mmol/L in 24 hours, 12 to 14 mmol/L in 48 hours, and 14 to 16 mmol/L in 72 hours.

A formula designed to predict the increase in serum Na⁺ concentration to be expected from the infusion of 1 L of a given infusion is given below: 1

Heart failure is a common and growing problem in both industrialized and developing nations. In the U.S. alone there are estimated to be well over 5 million heart failure patients and that number is expected to double over the next few decades. There are several reasons for this pandemic, most notably the aging of the world's population, a rising incidence of heart failure risk factors including hypertension, diabetes and obesity, and improved survival post‐myocardial infarction (MI).1 Greater longevity of patients with existing heart failure as a result of treatment with drugs and devices that lower mortality and, in developing nations, a reduction in premature mortality from infectious diseases have also contributed to the increase in heart failure prevalence. Although there have been important advances in treating heart failure that have improved outcomes over the past several decades, morbidity and mortality remain unacceptably high and quality of life is substantially reduced. Thus, there is considerable need for finding new approaches for managing patients with this condition.

The Role of Neurohormonal Blockade in the Treatment of Heart Failure Patients

The pathophysiology of heart failure is complex. In patients who develop systolic dysfunction, the pathway initially involves injury to the heart and/or increases in wall stress which activates a variety of compensatory responses in an effort to reestablish homeostasis within the cardiovascular (CV) system. Many of these responses are mediated by neurohormonal systems that are stimulated both systemically and locally within the heart itself.2, 3 While this widespread neurohormonal activation has some short‐term benefits in maintaining cardiac performance, there is clear evidence that it has adverse effects when maintained over time. The deleterious effects of neurohormonal activation in heart failure include excess salt and water retention, constriction of arterial resistance and venous capacitance vessels, increased load on the heart, electrolyte abnormalities and maladaptive cardiac remodeling. The critical role of neurohormonal activation in the pathogenesis and progression of heart failure has been confirmed by the results of large scale clinical trials which show that neurohormonal blocking agents such as angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), beta blockers (BBs), and aldosterone blockers greatly reduce morbidity and mortality and result in a variety of other favorable effects in heart failure patients.49 Based on their profound effects on outcomes, strategies that target neurohormonal activation have emerged over the past 2 decades as the cornerstone of medical management of heart failure.

Establishing Risk in Heart Failure

Although there have been impressive gains in reducing morbidity and mortality in heart failure patients over the past 3 decades, the overall clinical course remains unfavorable in a substantial portion of this population. A wide variety of risk factors which identify patients who are more likely to do poorly in the future have been identified. These include demographic variables (eg, age), functional and structural abnormalities, hemodynamic measurements, symptomatic status, exercise capacity, quality of life, presence of comorbidities and a myriad of blood tests and biomarkers. Amongst the plethora of risk factors for poor outcome, decompensation of heart failure which results in hospitalization has been recognized as 1 of the most important prognostic indicators. The Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE‐HF) Registry which included a large fairly representative population of heart failure patients from throughout the U.S. followed a subset of patients for 60 days to 90 days immediately post‐discharge from a hospitalization that was associated with decompensated heart failure.10 Over this relatively short time period hospital readmission rate was over 30% and mortality over 9%. Thus, within 2 months to 3 months of discharge following an episode of decompensation 40% of heart failure patients had either died or were back in the hospital. Among the many risk factors that have been used to predict morbidity and mortality outcomes either during or following hospitalization, the ones that appear to be the most powerful in detecting patients who are likely to do poorly are impaired renal function,11, 12 low systolic blood pressure,13 persistence of congestion at the time of hospital discharge,14 elevation of various biomarkers such as B‐type natriuretic peptide (BNP)15 and the presence of hyponatremia.16

Hyponatremia in Heart Failure

Incidence of Hyponatremia in Heart Failure Patients

Determining the exact incidence of hyponatremia in heart failure patients has been challenging due to differences in the populations that have been studied and in the criteria used to define hyponatremia. The Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure (ACTIV in CHF) study reported that 21.3% of the cohort of hospitalized patients had a serum sodium below 136 mmol/L.17 Higher incidences were reported in the Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME‐CHF) which found that 27% of patients had serum sodium concentrations between 132 mmol/L to 135 mmol/L.18 The Evaluation Study of CHF and Pulmonary Artery Catheter Effectiveness (ESCAPE) trial reported that 18% of patients had hyponatremia defined as serum sodium concentration below 134 mmol/L.19 Data from OPTIMIZE‐HF, a registry that captured data from a large cohort of representative patients who were hospitalized with decompensated heart failure indicate that such patients have a wide distribution of admission sodium values (Figure 1).16 Overall, 19.7% of the OPTIIMIZE‐HF patients had values below 135 mmol/L.

Figure 1

Risk Associated With Hyponatremia

There is considerable evidence that hyponatremia is associated with increased risk for poor outcomes in heart failure patients. One of the first reports that related hyponatremia to a poor prognosis came from Lee and Packer who analyzed 30 clinical, hemodynamic, and biochemical variables in outpatients with severe heart failure.20 Their results showed that serum sodium was the most powerful predictor of CV mortality. Similar findings have been reported by other investigators.21 In patients hospitalized for decompensated heart failure, the presence of hyponatremia has been shown to be an independent predictor of longer duration of stay.22 Results from the OPTIMIZE‐HF Registry confirmed the adverse impact of hyponatremia on length of stay during a heart failure hospitalization and also suggested that low serum sodium was associated with significantly higher in‐hospital and post‐discharge mortality rates.16 In this large cohort of hospitalized patients with decompensated heart failure, each 3 mmol/L decrease in serum sodium below 140 mmol/L increased the risk of in‐hospital and follow‐up mortality by 19.5% and 10%, respectively. This association is depicted in Figure 2. A similar adverse impact of hyponatremia on post‐discharge outcomes was seen in the results of the ACTIV in CHF study.17 Overall, 69 patients out of a total of 319 who were included in the study (21.6%) had a serum sodium that was 136 mmol/L. Mortality over a 60 day period of follow‐up was 14.5% in the hyponatremic patients compared to 4% in the 250 patients whose serum sodium was 136 mmol/L.

Figure 2

Although these data present a powerful argument that hyponatremia is a potent risk factor for poor outcomes in heart failure patients both during and following hospitalization, they do not determine whether or not the relationship is causal. It is possible that the poor outcomes that have been observed in hyponatremic patients are related to an association between low serum sodium levels and the more profound alterations in hemodynamics, neurohormonal activation and renal function that are seen in patients with advanced heart failure. Alternatively, increased edema in vital organs including the heart in hyponatremic patients could further impair already tenuous function and contribute to a downward spiral in the clinical course. The impact of hyponatremia in limiting the use of loop diuretics and spironolactone may also be associated with a less favorable long‐term outcome. The presence of hyponatremia may also contribute to a poor outcome as a result of effects on cognitive and neuromuscular function.23, 24 Impaired cognition could adversely affect compliance with the medical regimen while neuromuscular problems related to hyponatremia could contribute to an increased incidence of falls and other traumatic injuries that older patients with chronic diseases are already at high risk of experiencing.

The Use of Vaptans in Treating Hyponatremia

AVP actions are mediated by an interaction of the peptide with a series of receptors located on cells throughout the body. Vaptans are nonpeptidergic agents which block the interaction of AVP with these receptors; they are classified according to which receptor subtype they affect. As mentioned earlier, activation of the V2 receptor on renal tubular cells increases collecting duct permeability to water and leads to reabsorption of free water.35 The V1A receptor is located on vascular smooth muscle cells where it mediates an increase in vasomotor tone. V1A receptors are also found on platelets and in the myometrium where they mediate aggregation and uterine contraction, respectively. Some of the AVP antagonists (eg, conivaptan) block both the V1A and V2 receptors while others (eg, tolvaptan and lixivaptan) are selective for the V2 receptor.

Tolvaptan, a V2 selective agent, has been studied extensively in heart failure as well as in patients with hyponatremia due to a variety of causes. One of the initial studies was performed in a group of 254 heart failure patients who were randomized to receive tolvaptan in doses ranging from 30 mg to 60 mg daily or placebo.36 Tolvaptan at all doses studied was associated with significant reductions in body weight and improvement in the signs and symptoms of heart failure. All doses were also associated with an increase in serum sodium levels in this study. Patients who were hyponatremic made up 28% of the study population and these patients experienced the greatest increase in serum sodium. Of note was the fact that as early as day 1 in the study 80% of tolvaptan (as opposed to 40% of placebo) patients had normalization of their serum sodium levels. These effects occurred without significant changes in blood pressure or renal function and the major side effects that were seen were polyuria, dry mouth, and thirst. This study was followed by the ACTIV in CHF trial which included a slightly larger population of 319 patients (of whom 21.3% were hyponatremic at baseline) who were hospitalized due to decompensated heart failure.17 Mean body weight decreased significantly more in patients treated with tolvaptan compared to those who received placebo. Tolvaptan‐treated patients also experienced increases in serum sodium that were greatest in the patients who were hyponatremic at baseline. These changes persisted throughout the duration of the study. On post hoc analysis, event‐free survival tended to be longer for the combined group of patients treated with tolvaptan compared to placebo but there were no differences in the rate of rehospitalization or unscheduled visits for heart failure. As in the initial study, tolvaptan was well tolerated, with dry mouth being the main side effect. There were no significant hemodynamic or renal effects.

The efficacy of vasopressin antagonism in heart failure outcome study with tolvaptan (EVEREST) study randomized 4133 patients hospitalized for decompensated heart failure to receive either tolvaptan 30 mg daily or placebo in addition to their standard therapy. The short‐term goal of the study was to assess the effects of therapy on a composite end‐point of patient assessed global clinical features and weight loss on day 7 (or at the time of hospital discharge) after starting treatment.37 The results of EVEREST demonstrated that patients treated with tolvaptan had greater improvement in the composite primary end‐point. This effect was driven by a greater reduction in body weight with active drug. Although, changes in global clinical status did not differ between the study groups, tolvaptan‐treated patients reported significantly greater improvement in dyspnea at day 1. In 1 (but not the other of the 2 component trials of EVEREST) there was also an improvement in edema. At day 1 and at discharge, the tolvaptan group with hyponatremia (defined as a serum sodium below 134 mEq/L) demonstrated significantly greater increases in serum sodium than in the hyponatremic placebo treated patients. Tolvaptan was well tolerated and serious adverse event frequencies were similar between groups, without excess renal failure or hypotension.

Patients who were enrolled in EVEREST were then followed for an average of 9.9 months on tolvaptan or placebo in order to assess the effects of treatment on the dual primary endpoints of all‐cause mortality (both superiority and noninferiority) and CV death or heart failure hospitalization.38 The results demonstrated no significant differences in either primary or secondary morbidity and mortality outcomes between tolvaptan and placebo treated patients. In the EVEREST patients with baseline serum sodium levels less than 134 mEq/L, there was a significant increase of 5.49 mEq/L 5.77 mEq/L (mean SD) at day 7 or discharge, if earlier, with tolvaptan, compared with 1.85 mEq/L 5.10 mEq/L in the placebo group. This effect was observed as early as day 1 and was maintained throughout the 40 weeks of treatment. Side effects were minimal. Overall, tolvaptan increased thirst and dry mouth, but the frequencies of major adverse events were similar in the 2 groups.

Two parallel multicenter, randomized, double‐blind, placebo‐controlled trials, termed collectively the Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2 (SALT‐1 and SALT‐2), examined the effect of tolvaptan on hypervolemic and euvolemic hyponatremia of diverse causes.39 The 448 patients included in the 2 studies were randomly assigned to either placebo or tolvaptan starting at a dose of 15 mg daily (increasing to 30 mg and then 60 mg if needed, depending on serum sodium concentrations) and followed over a 30 day period. The population included 138 patients (31%) with chronic heart failure as the cause of hyponatremia with the remainder of the population divided between patients with cirrhosis or syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH) and other causes of hyponatremia. The 2 primary end points for all patients were the change in the average daily area under the curve for the serum sodium concentration from baseline to day 4 and the change from baseline to day 30. As shown in Figure 3, serum sodium concentrations increased significantly more in the tolvaptan group than in the placebo group during the first 4 days and after the full 30 days of therapy. A planned analysis of the SALT trials demonstrated that correction of hyponatremia with tolvaptan was associated with significant improvement in self‐reported mental status, particularly in patients with marked hyponatremia or SIADH. Improvements in mental health scores were positively correlated with changes in serum [Na+] in both the tolvaptan and placebo groups and reversed after cessation of therapy, suggeting that hyponatremia‐associated impairments in mental function can be significantly improved by raising the serum [Na+]. The major side effects with tolvaptan included increased thirst, dry mouth, and increased urination. Tolvaptan has been approved by the US Food and Drug Administration (FDA) for the treatment of euvolemic and hypervolemic hyponatremia.

Figure 3

Lixivaptan is another selective V2 receptor antagonist that has been studied in heart failure patients.40 In a randomized, double‐blind, placebo‐controlled, ascending single‐dose study 42 diuretic‐requiring patients with mild‐to‐moderate heart failure patients received either placebo or doses of lixivaptan ranging from 10 mg to 400 mg. Except for patients who received the 10‐mg dose, lixivaptan produced a significant and dose‐related increase in urine volume over a 4‐hour period compared with placebo. Over 24 hours increases in urine volume were greater with lixivaptan than with placebo and these increases were accompanied by significant increases in solute‐free water excretion. At higher doses of lixivaptan, serum sodium levels increased significantly. The drug was tolerated in these patients and side effects tended to be mild. The Treatment of Hyponatremia Based on Lixivaptan in NYHA Class III/IV Cardiac Patient Evaluation (BALANCE Study) is an on‐going trial that is designed to evaluate whether lixivaptan is an effective and safe agent for increasing serum sodium in heart failure patients who are volume overloaded and have hyponatremia. The secondary end‐points of the BALANCE study include all‐cause mortality, CV effects, HF hospitalization and acute change in body weight.

The combined V1A and V2 receptor antagonist conivaptan has been approved by the FDA for the treatment of euvolemic and hypervolemic hyponatremia. The acute hemodynamic effects were studied in 142 NYHA class III and IV heart failure patients. Administration of 20 mg or 40 mg of conivaptan significantly reduced pulmonary artery wedge and right atrial pressures during the 3‐hour to 6‐hour interval after intravenous administration and significantly increased urine output in a dose‐dependent manner during the first 4 hours after the dose.41 In another study 170 patients hospitalized for worsening heart failure were randomly assigned to treatment with conivaptan (20‐mg loading dose followed by 2 successive 24‐hour continuous infusions of 40, 80, or 120 mg/day) or placebo in addition to their standard therapy.42 At 24 hours each dose of conivaptan had increased urine output significantly more than placebo with the difference averaging 1.0 to 1.5 L. The mean increase in serum sodium at 24, 48, and 72 hours was significantly higher in each of the conivaptan groups compared with the placebo group. At 48 hours, conivaptan increased serum sodium by 2.25 mmol/L to 3.27 mmol/L more than placebo. Conivaptan was well tolerated in these hospitalized heart failure patients. Infusion‐site reactions for this drug which is given intravenously were the most common adverse event and administration of the drug was not associated with clinically important changes in vital signs, electrolyte disturbances, or cardiac rhythm.

The effects of conivaptan on serum sodium levels were evaluated in 84 hospitalized patients with euvolemic or hypervolemic hyponatremia defined as a serum sodium between 115 mEq/ to 129 mEq/L.43 These patients received either intravenous placebo or conivaptan administered as a 30‐minute, 20‐mg loading dose followed by a 96‐hour infusion of either 40 mg/day or 80 mg/day. The results which are depicted in Figure 4 show that both conivaptan doses were associated with highly significant increases under the sodium‐time curve during the 4‐day treatment. From baseline to the end of treatment, serum sodium increased by 0.8 0.8 mEq/L with placebo as compared to 6.3 0.7 mEq/L and 9.4 0.8 mEq/L with the 40 mg and 80 mg doses of conivaptan. Conivaptan was generally well tolerated, although infusion‐site reactions led to the withdrawal of 1 (3%) and 4 (15%) of patients given conivaptan 40 mg/day and 80 mg/day, respectively.

Figure 4

The overall safety profile of the vaptans has been good. Most of the adverse effects including thirst, dry mouth and others have been minor and these agents, in general, have only minimal effects on blood pressure and renal function. In addition, the long‐term safety and tolerability of tolvaptan was demonstrated in the EVEREST trial. One theoretical concern about the use of vaptans to treat hyponatremia is that rapid correction of hyponatremia at a rate of >12 mEq/L over 24 hours can cause osmotic demyelination of brain structures with severe neurologic consequences. It has been advised that in susceptible patients (including those with severe malnutrition, alcoholism, or advanced liver disease) that sodium levels be corrected at a lower rate. It is also recommended that the drugs be initiated in hospital and that serum sodium is monitored during treatment.

Conclusions

Hyponatremia is common in heart failure patients, particularly during periods of decompensation. The presence of hyponatremia has been associated with a substantial increase in risk for longer hospitalization stay and mortality both in the hospital and following discharge. Hyponatremia has also been associated with alterations in cognitive and neuromuscular function which could further impair heart failure patients, particularly those who are elderly. The use of AVP receptor antagonists to treat hyponatremia is based on evidence that this peptide which regulates the flow of free water in the distal portion of the nephron is inappropriately elevated in heart failure patients. Administration of AVP receptor antagonists has been shown to increase and improve free water excretion and increase serum sodium levels in both euvolemic and volume overloaded hyponatremic patients. In addition to their favorable effects on serum sodium levels, the AVP receptor blockers have been shown to improve hemodynamics acutely and to increase weight loss in heart failure patients. There is some evidence that they also improve symptoms in hospitalized patients and that correction of hyponatremia is associated with improved cognitive and neuromuscular function. Currently available evidence, however, does not support a beneficial effect on long‐term outcomes such as mortality or CV hospitalizations. Additional on‐going clinical trials will provide further insights into this critical question. The overall side effect profile of the vaptans is favorable and published studies document the long‐term safety of administration of tolvaptan in heart failure patients. Thus, these agents represent an important new approach for treating hyponatremia in heart failure patients. They deserve consideration for use when hyponatremia is present during an episode of decompensated heart failure.

Heart failure is a common and growing problem in both industrialized and developing nations. In the U.S. alone there are estimated to be well over 5 million heart failure patients and that number is expected to double over the next few decades. There are several reasons for this pandemic, most notably the aging of the world's population, a rising incidence of heart failure risk factors including hypertension, diabetes and obesity, and improved survival post‐myocardial infarction (MI).1 Greater longevity of patients with existing heart failure as a result of treatment with drugs and devices that lower mortality and, in developing nations, a reduction in premature mortality from infectious diseases have also contributed to the increase in heart failure prevalence. Although there have been important advances in treating heart failure that have improved outcomes over the past several decades, morbidity and mortality remain unacceptably high and quality of life is substantially reduced. Thus, there is considerable need for finding new approaches for managing patients with this condition.

The Role of Neurohormonal Blockade in the Treatment of Heart Failure Patients

The pathophysiology of heart failure is complex. In patients who develop systolic dysfunction, the pathway initially involves injury to the heart and/or increases in wall stress which activates a variety of compensatory responses in an effort to reestablish homeostasis within the cardiovascular (CV) system. Many of these responses are mediated by neurohormonal systems that are stimulated both systemically and locally within the heart itself.2, 3 While this widespread neurohormonal activation has some short‐term benefits in maintaining cardiac performance, there is clear evidence that it has adverse effects when maintained over time. The deleterious effects of neurohormonal activation in heart failure include excess salt and water retention, constriction of arterial resistance and venous capacitance vessels, increased load on the heart, electrolyte abnormalities and maladaptive cardiac remodeling. The critical role of neurohormonal activation in the pathogenesis and progression of heart failure has been confirmed by the results of large scale clinical trials which show that neurohormonal blocking agents such as angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), beta blockers (BBs), and aldosterone blockers greatly reduce morbidity and mortality and result in a variety of other favorable effects in heart failure patients.49 Based on their profound effects on outcomes, strategies that target neurohormonal activation have emerged over the past 2 decades as the cornerstone of medical management of heart failure.

Establishing Risk in Heart Failure

Although there have been impressive gains in reducing morbidity and mortality in heart failure patients over the past 3 decades, the overall clinical course remains unfavorable in a substantial portion of this population. A wide variety of risk factors which identify patients who are more likely to do poorly in the future have been identified. These include demographic variables (eg, age), functional and structural abnormalities, hemodynamic measurements, symptomatic status, exercise capacity, quality of life, presence of comorbidities and a myriad of blood tests and biomarkers. Amongst the plethora of risk factors for poor outcome, decompensation of heart failure which results in hospitalization has been recognized as 1 of the most important prognostic indicators. The Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE‐HF) Registry which included a large fairly representative population of heart failure patients from throughout the U.S. followed a subset of patients for 60 days to 90 days immediately post‐discharge from a hospitalization that was associated with decompensated heart failure.10 Over this relatively short time period hospital readmission rate was over 30% and mortality over 9%. Thus, within 2 months to 3 months of discharge following an episode of decompensation 40% of heart failure patients had either died or were back in the hospital. Among the many risk factors that have been used to predict morbidity and mortality outcomes either during or following hospitalization, the ones that appear to be the most powerful in detecting patients who are likely to do poorly are impaired renal function,11, 12 low systolic blood pressure,13 persistence of congestion at the time of hospital discharge,14 elevation of various biomarkers such as B‐type natriuretic peptide (BNP)15 and the presence of hyponatremia.16

Hyponatremia in Heart Failure

Incidence of Hyponatremia in Heart Failure Patients

Determining the exact incidence of hyponatremia in heart failure patients has been challenging due to differences in the populations that have been studied and in the criteria used to define hyponatremia. The Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure (ACTIV in CHF) study reported that 21.3% of the cohort of hospitalized patients had a serum sodium below 136 mmol/L.17 Higher incidences were reported in the Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME‐CHF) which found that 27% of patients had serum sodium concentrations between 132 mmol/L to 135 mmol/L.18 The Evaluation Study of CHF and Pulmonary Artery Catheter Effectiveness (ESCAPE) trial reported that 18% of patients had hyponatremia defined as serum sodium concentration below 134 mmol/L.19 Data from OPTIMIZE‐HF, a registry that captured data from a large cohort of representative patients who were hospitalized with decompensated heart failure indicate that such patients have a wide distribution of admission sodium values (Figure 1).16 Overall, 19.7% of the OPTIIMIZE‐HF patients had values below 135 mmol/L.

Figure 1

Risk Associated With Hyponatremia

There is considerable evidence that hyponatremia is associated with increased risk for poor outcomes in heart failure patients. One of the first reports that related hyponatremia to a poor prognosis came from Lee and Packer who analyzed 30 clinical, hemodynamic, and biochemical variables in outpatients with severe heart failure.20 Their results showed that serum sodium was the most powerful predictor of CV mortality. Similar findings have been reported by other investigators.21 In patients hospitalized for decompensated heart failure, the presence of hyponatremia has been shown to be an independent predictor of longer duration of stay.22 Results from the OPTIMIZE‐HF Registry confirmed the adverse impact of hyponatremia on length of stay during a heart failure hospitalization and also suggested that low serum sodium was associated with significantly higher in‐hospital and post‐discharge mortality rates.16 In this large cohort of hospitalized patients with decompensated heart failure, each 3 mmol/L decrease in serum sodium below 140 mmol/L increased the risk of in‐hospital and follow‐up mortality by 19.5% and 10%, respectively. This association is depicted in Figure 2. A similar adverse impact of hyponatremia on post‐discharge outcomes was seen in the results of the ACTIV in CHF study.17 Overall, 69 patients out of a total of 319 who were included in the study (21.6%) had a serum sodium that was 136 mmol/L. Mortality over a 60 day period of follow‐up was 14.5% in the hyponatremic patients compared to 4% in the 250 patients whose serum sodium was 136 mmol/L.

Figure 2

Although these data present a powerful argument that hyponatremia is a potent risk factor for poor outcomes in heart failure patients both during and following hospitalization, they do not determine whether or not the relationship is causal. It is possible that the poor outcomes that have been observed in hyponatremic patients are related to an association between low serum sodium levels and the more profound alterations in hemodynamics, neurohormonal activation and renal function that are seen in patients with advanced heart failure. Alternatively, increased edema in vital organs including the heart in hyponatremic patients could further impair already tenuous function and contribute to a downward spiral in the clinical course. The impact of hyponatremia in limiting the use of loop diuretics and spironolactone may also be associated with a less favorable long‐term outcome. The presence of hyponatremia may also contribute to a poor outcome as a result of effects on cognitive and neuromuscular function.23, 24 Impaired cognition could adversely affect compliance with the medical regimen while neuromuscular problems related to hyponatremia could contribute to an increased incidence of falls and other traumatic injuries that older patients with chronic diseases are already at high risk of experiencing.

The Use of Vaptans in Treating Hyponatremia

AVP actions are mediated by an interaction of the peptide with a series of receptors located on cells throughout the body. Vaptans are nonpeptidergic agents which block the interaction of AVP with these receptors; they are classified according to which receptor subtype they affect. As mentioned earlier, activation of the V2 receptor on renal tubular cells increases collecting duct permeability to water and leads to reabsorption of free water.35 The V1A receptor is located on vascular smooth muscle cells where it mediates an increase in vasomotor tone. V1A receptors are also found on platelets and in the myometrium where they mediate aggregation and uterine contraction, respectively. Some of the AVP antagonists (eg, conivaptan) block both the V1A and V2 receptors while others (eg, tolvaptan and lixivaptan) are selective for the V2 receptor.

Tolvaptan, a V2 selective agent, has been studied extensively in heart failure as well as in patients with hyponatremia due to a variety of causes. One of the initial studies was performed in a group of 254 heart failure patients who were randomized to receive tolvaptan in doses ranging from 30 mg to 60 mg daily or placebo.36 Tolvaptan at all doses studied was associated with significant reductions in body weight and improvement in the signs and symptoms of heart failure. All doses were also associated with an increase in serum sodium levels in this study. Patients who were hyponatremic made up 28% of the study population and these patients experienced the greatest increase in serum sodium. Of note was the fact that as early as day 1 in the study 80% of tolvaptan (as opposed to 40% of placebo) patients had normalization of their serum sodium levels. These effects occurred without significant changes in blood pressure or renal function and the major side effects that were seen were polyuria, dry mouth, and thirst. This study was followed by the ACTIV in CHF trial which included a slightly larger population of 319 patients (of whom 21.3% were hyponatremic at baseline) who were hospitalized due to decompensated heart failure.17 Mean body weight decreased significantly more in patients treated with tolvaptan compared to those who received placebo. Tolvaptan‐treated patients also experienced increases in serum sodium that were greatest in the patients who were hyponatremic at baseline. These changes persisted throughout the duration of the study. On post hoc analysis, event‐free survival tended to be longer for the combined group of patients treated with tolvaptan compared to placebo but there were no differences in the rate of rehospitalization or unscheduled visits for heart failure. As in the initial study, tolvaptan was well tolerated, with dry mouth being the main side effect. There were no significant hemodynamic or renal effects.

The efficacy of vasopressin antagonism in heart failure outcome study with tolvaptan (EVEREST) study randomized 4133 patients hospitalized for decompensated heart failure to receive either tolvaptan 30 mg daily or placebo in addition to their standard therapy. The short‐term goal of the study was to assess the effects of therapy on a composite end‐point of patient assessed global clinical features and weight loss on day 7 (or at the time of hospital discharge) after starting treatment.37 The results of EVEREST demonstrated that patients treated with tolvaptan had greater improvement in the composite primary end‐point. This effect was driven by a greater reduction in body weight with active drug. Although, changes in global clinical status did not differ between the study groups, tolvaptan‐treated patients reported significantly greater improvement in dyspnea at day 1. In 1 (but not the other of the 2 component trials of EVEREST) there was also an improvement in edema. At day 1 and at discharge, the tolvaptan group with hyponatremia (defined as a serum sodium below 134 mEq/L) demonstrated significantly greater increases in serum sodium than in the hyponatremic placebo treated patients. Tolvaptan was well tolerated and serious adverse event frequencies were similar between groups, without excess renal failure or hypotension.

Patients who were enrolled in EVEREST were then followed for an average of 9.9 months on tolvaptan or placebo in order to assess the effects of treatment on the dual primary endpoints of all‐cause mortality (both superiority and noninferiority) and CV death or heart failure hospitalization.38 The results demonstrated no significant differences in either primary or secondary morbidity and mortality outcomes between tolvaptan and placebo treated patients. In the EVEREST patients with baseline serum sodium levels less than 134 mEq/L, there was a significant increase of 5.49 mEq/L 5.77 mEq/L (mean SD) at day 7 or discharge, if earlier, with tolvaptan, compared with 1.85 mEq/L 5.10 mEq/L in the placebo group. This effect was observed as early as day 1 and was maintained throughout the 40 weeks of treatment. Side effects were minimal. Overall, tolvaptan increased thirst and dry mouth, but the frequencies of major adverse events were similar in the 2 groups.

Two parallel multicenter, randomized, double‐blind, placebo‐controlled trials, termed collectively the Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2 (SALT‐1 and SALT‐2), examined the effect of tolvaptan on hypervolemic and euvolemic hyponatremia of diverse causes.39 The 448 patients included in the 2 studies were randomly assigned to either placebo or tolvaptan starting at a dose of 15 mg daily (increasing to 30 mg and then 60 mg if needed, depending on serum sodium concentrations) and followed over a 30 day period. The population included 138 patients (31%) with chronic heart failure as the cause of hyponatremia with the remainder of the population divided between patients with cirrhosis or syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH) and other causes of hyponatremia. The 2 primary end points for all patients were the change in the average daily area under the curve for the serum sodium concentration from baseline to day 4 and the change from baseline to day 30. As shown in Figure 3, serum sodium concentrations increased significantly more in the tolvaptan group than in the placebo group during the first 4 days and after the full 30 days of therapy. A planned analysis of the SALT trials demonstrated that correction of hyponatremia with tolvaptan was associated with significant improvement in self‐reported mental status, particularly in patients with marked hyponatremia or SIADH. Improvements in mental health scores were positively correlated with changes in serum [Na+] in both the tolvaptan and placebo groups and reversed after cessation of therapy, suggeting that hyponatremia‐associated impairments in mental function can be significantly improved by raising the serum [Na+]. The major side effects with tolvaptan included increased thirst, dry mouth, and increased urination. Tolvaptan has been approved by the US Food and Drug Administration (FDA) for the treatment of euvolemic and hypervolemic hyponatremia.

Figure 3

Lixivaptan is another selective V2 receptor antagonist that has been studied in heart failure patients.40 In a randomized, double‐blind, placebo‐controlled, ascending single‐dose study 42 diuretic‐requiring patients with mild‐to‐moderate heart failure patients received either placebo or doses of lixivaptan ranging from 10 mg to 400 mg. Except for patients who received the 10‐mg dose, lixivaptan produced a significant and dose‐related increase in urine volume over a 4‐hour period compared with placebo. Over 24 hours increases in urine volume were greater with lixivaptan than with placebo and these increases were accompanied by significant increases in solute‐free water excretion. At higher doses of lixivaptan, serum sodium levels increased significantly. The drug was tolerated in these patients and side effects tended to be mild. The Treatment of Hyponatremia Based on Lixivaptan in NYHA Class III/IV Cardiac Patient Evaluation (BALANCE Study) is an on‐going trial that is designed to evaluate whether lixivaptan is an effective and safe agent for increasing serum sodium in heart failure patients who are volume overloaded and have hyponatremia. The secondary end‐points of the BALANCE study include all‐cause mortality, CV effects, HF hospitalization and acute change in body weight.

The combined V1A and V2 receptor antagonist conivaptan has been approved by the FDA for the treatment of euvolemic and hypervolemic hyponatremia. The acute hemodynamic effects were studied in 142 NYHA class III and IV heart failure patients. Administration of 20 mg or 40 mg of conivaptan significantly reduced pulmonary artery wedge and right atrial pressures during the 3‐hour to 6‐hour interval after intravenous administration and significantly increased urine output in a dose‐dependent manner during the first 4 hours after the dose.41 In another study 170 patients hospitalized for worsening heart failure were randomly assigned to treatment with conivaptan (20‐mg loading dose followed by 2 successive 24‐hour continuous infusions of 40, 80, or 120 mg/day) or placebo in addition to their standard therapy.42 At 24 hours each dose of conivaptan had increased urine output significantly more than placebo with the difference averaging 1.0 to 1.5 L. The mean increase in serum sodium at 24, 48, and 72 hours was significantly higher in each of the conivaptan groups compared with the placebo group. At 48 hours, conivaptan increased serum sodium by 2.25 mmol/L to 3.27 mmol/L more than placebo. Conivaptan was well tolerated in these hospitalized heart failure patients. Infusion‐site reactions for this drug which is given intravenously were the most common adverse event and administration of the drug was not associated with clinically important changes in vital signs, electrolyte disturbances, or cardiac rhythm.

The effects of conivaptan on serum sodium levels were evaluated in 84 hospitalized patients with euvolemic or hypervolemic hyponatremia defined as a serum sodium between 115 mEq/ to 129 mEq/L.43 These patients received either intravenous placebo or conivaptan administered as a 30‐minute, 20‐mg loading dose followed by a 96‐hour infusion of either 40 mg/day or 80 mg/day. The results which are depicted in Figure 4 show that both conivaptan doses were associated with highly significant increases under the sodium‐time curve during the 4‐day treatment. From baseline to the end of treatment, serum sodium increased by 0.8 0.8 mEq/L with placebo as compared to 6.3 0.7 mEq/L and 9.4 0.8 mEq/L with the 40 mg and 80 mg doses of conivaptan. Conivaptan was generally well tolerated, although infusion‐site reactions led to the withdrawal of 1 (3%) and 4 (15%) of patients given conivaptan 40 mg/day and 80 mg/day, respectively.

Figure 4

The overall safety profile of the vaptans has been good. Most of the adverse effects including thirst, dry mouth and others have been minor and these agents, in general, have only minimal effects on blood pressure and renal function. In addition, the long‐term safety and tolerability of tolvaptan was demonstrated in the EVEREST trial. One theoretical concern about the use of vaptans to treat hyponatremia is that rapid correction of hyponatremia at a rate of >12 mEq/L over 24 hours can cause osmotic demyelination of brain structures with severe neurologic consequences. It has been advised that in susceptible patients (including those with severe malnutrition, alcoholism, or advanced liver disease) that sodium levels be corrected at a lower rate. It is also recommended that the drugs be initiated in hospital and that serum sodium is monitored during treatment.

Conclusions

Hyponatremia is common in heart failure patients, particularly during periods of decompensation. The presence of hyponatremia has been associated with a substantial increase in risk for longer hospitalization stay and mortality both in the hospital and following discharge. Hyponatremia has also been associated with alterations in cognitive and neuromuscular function which could further impair heart failure patients, particularly those who are elderly. The use of AVP receptor antagonists to treat hyponatremia is based on evidence that this peptide which regulates the flow of free water in the distal portion of the nephron is inappropriately elevated in heart failure patients. Administration of AVP receptor antagonists has been shown to increase and improve free water excretion and increase serum sodium levels in both euvolemic and volume overloaded hyponatremic patients. In addition to their favorable effects on serum sodium levels, the AVP receptor blockers have been shown to improve hemodynamics acutely and to increase weight loss in heart failure patients. There is some evidence that they also improve symptoms in hospitalized patients and that correction of hyponatremia is associated with improved cognitive and neuromuscular function. Currently available evidence, however, does not support a beneficial effect on long‐term outcomes such as mortality or CV hospitalizations. Additional on‐going clinical trials will provide further insights into this critical question. The overall side effect profile of the vaptans is favorable and published studies document the long‐term safety of administration of tolvaptan in heart failure patients. Thus, these agents represent an important new approach for treating hyponatremia in heart failure patients. They deserve consideration for use when hyponatremia is present during an episode of decompensated heart failure.

Heart failure is a common and growing problem in both industrialized and developing nations. In the U.S. alone there are estimated to be well over 5 million heart failure patients and that number is expected to double over the next few decades. There are several reasons for this pandemic, most notably the aging of the world's population, a rising incidence of heart failure risk factors including hypertension, diabetes and obesity, and improved survival post‐myocardial infarction (MI).1 Greater longevity of patients with existing heart failure as a result of treatment with drugs and devices that lower mortality and, in developing nations, a reduction in premature mortality from infectious diseases have also contributed to the increase in heart failure prevalence. Although there have been important advances in treating heart failure that have improved outcomes over the past several decades, morbidity and mortality remain unacceptably high and quality of life is substantially reduced. Thus, there is considerable need for finding new approaches for managing patients with this condition.

The Role of Neurohormonal Blockade in the Treatment of Heart Failure Patients

The pathophysiology of heart failure is complex. In patients who develop systolic dysfunction, the pathway initially involves injury to the heart and/or increases in wall stress which activates a variety of compensatory responses in an effort to reestablish homeostasis within the cardiovascular (CV) system. Many of these responses are mediated by neurohormonal systems that are stimulated both systemically and locally within the heart itself.2, 3 While this widespread neurohormonal activation has some short‐term benefits in maintaining cardiac performance, there is clear evidence that it has adverse effects when maintained over time. The deleterious effects of neurohormonal activation in heart failure include excess salt and water retention, constriction of arterial resistance and venous capacitance vessels, increased load on the heart, electrolyte abnormalities and maladaptive cardiac remodeling. The critical role of neurohormonal activation in the pathogenesis and progression of heart failure has been confirmed by the results of large scale clinical trials which show that neurohormonal blocking agents such as angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), beta blockers (BBs), and aldosterone blockers greatly reduce morbidity and mortality and result in a variety of other favorable effects in heart failure patients.49 Based on their profound effects on outcomes, strategies that target neurohormonal activation have emerged over the past 2 decades as the cornerstone of medical management of heart failure.

Establishing Risk in Heart Failure

Although there have been impressive gains in reducing morbidity and mortality in heart failure patients over the past 3 decades, the overall clinical course remains unfavorable in a substantial portion of this population. A wide variety of risk factors which identify patients who are more likely to do poorly in the future have been identified. These include demographic variables (eg, age), functional and structural abnormalities, hemodynamic measurements, symptomatic status, exercise capacity, quality of life, presence of comorbidities and a myriad of blood tests and biomarkers. Amongst the plethora of risk factors for poor outcome, decompensation of heart failure which results in hospitalization has been recognized as 1 of the most important prognostic indicators. The Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE‐HF) Registry which included a large fairly representative population of heart failure patients from throughout the U.S. followed a subset of patients for 60 days to 90 days immediately post‐discharge from a hospitalization that was associated with decompensated heart failure.10 Over this relatively short time period hospital readmission rate was over 30% and mortality over 9%. Thus, within 2 months to 3 months of discharge following an episode of decompensation 40% of heart failure patients had either died or were back in the hospital. Among the many risk factors that have been used to predict morbidity and mortality outcomes either during or following hospitalization, the ones that appear to be the most powerful in detecting patients who are likely to do poorly are impaired renal function,11, 12 low systolic blood pressure,13 persistence of congestion at the time of hospital discharge,14 elevation of various biomarkers such as B‐type natriuretic peptide (BNP)15 and the presence of hyponatremia.16

Hyponatremia in Heart Failure

Incidence of Hyponatremia in Heart Failure Patients

Determining the exact incidence of hyponatremia in heart failure patients has been challenging due to differences in the populations that have been studied and in the criteria used to define hyponatremia. The Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure (ACTIV in CHF) study reported that 21.3% of the cohort of hospitalized patients had a serum sodium below 136 mmol/L.17 Higher incidences were reported in the Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME‐CHF) which found that 27% of patients had serum sodium concentrations between 132 mmol/L to 135 mmol/L.18 The Evaluation Study of CHF and Pulmonary Artery Catheter Effectiveness (ESCAPE) trial reported that 18% of patients had hyponatremia defined as serum sodium concentration below 134 mmol/L.19 Data from OPTIMIZE‐HF, a registry that captured data from a large cohort of representative patients who were hospitalized with decompensated heart failure indicate that such patients have a wide distribution of admission sodium values (Figure 1).16 Overall, 19.7% of the OPTIIMIZE‐HF patients had values below 135 mmol/L.

Figure 1

Risk Associated With Hyponatremia

There is considerable evidence that hyponatremia is associated with increased risk for poor outcomes in heart failure patients. One of the first reports that related hyponatremia to a poor prognosis came from Lee and Packer who analyzed 30 clinical, hemodynamic, and biochemical variables in outpatients with severe heart failure.20 Their results showed that serum sodium was the most powerful predictor of CV mortality. Similar findings have been reported by other investigators.21 In patients hospitalized for decompensated heart failure, the presence of hyponatremia has been shown to be an independent predictor of longer duration of stay.22 Results from the OPTIMIZE‐HF Registry confirmed the adverse impact of hyponatremia on length of stay during a heart failure hospitalization and also suggested that low serum sodium was associated with significantly higher in‐hospital and post‐discharge mortality rates.16 In this large cohort of hospitalized patients with decompensated heart failure, each 3 mmol/L decrease in serum sodium below 140 mmol/L increased the risk of in‐hospital and follow‐up mortality by 19.5% and 10%, respectively. This association is depicted in Figure 2. A similar adverse impact of hyponatremia on post‐discharge outcomes was seen in the results of the ACTIV in CHF study.17 Overall, 69 patients out of a total of 319 who were included in the study (21.6%) had a serum sodium that was 136 mmol/L. Mortality over a 60 day period of follow‐up was 14.5% in the hyponatremic patients compared to 4% in the 250 patients whose serum sodium was 136 mmol/L.

Figure 2

Although these data present a powerful argument that hyponatremia is a potent risk factor for poor outcomes in heart failure patients both during and following hospitalization, they do not determine whether or not the relationship is causal. It is possible that the poor outcomes that have been observed in hyponatremic patients are related to an association between low serum sodium levels and the more profound alterations in hemodynamics, neurohormonal activation and renal function that are seen in patients with advanced heart failure. Alternatively, increased edema in vital organs including the heart in hyponatremic patients could further impair already tenuous function and contribute to a downward spiral in the clinical course. The impact of hyponatremia in limiting the use of loop diuretics and spironolactone may also be associated with a less favorable long‐term outcome. The presence of hyponatremia may also contribute to a poor outcome as a result of effects on cognitive and neuromuscular function.23, 24 Impaired cognition could adversely affect compliance with the medical regimen while neuromuscular problems related to hyponatremia could contribute to an increased incidence of falls and other traumatic injuries that older patients with chronic diseases are already at high risk of experiencing.

The Use of Vaptans in Treating Hyponatremia

AVP actions are mediated by an interaction of the peptide with a series of receptors located on cells throughout the body. Vaptans are nonpeptidergic agents which block the interaction of AVP with these receptors; they are classified according to which receptor subtype they affect. As mentioned earlier, activation of the V2 receptor on renal tubular cells increases collecting duct permeability to water and leads to reabsorption of free water.35 The V1A receptor is located on vascular smooth muscle cells where it mediates an increase in vasomotor tone. V1A receptors are also found on platelets and in the myometrium where they mediate aggregation and uterine contraction, respectively. Some of the AVP antagonists (eg, conivaptan) block both the V1A and V2 receptors while others (eg, tolvaptan and lixivaptan) are selective for the V2 receptor.

Tolvaptan, a V2 selective agent, has been studied extensively in heart failure as well as in patients with hyponatremia due to a variety of causes. One of the initial studies was performed in a group of 254 heart failure patients who were randomized to receive tolvaptan in doses ranging from 30 mg to 60 mg daily or placebo.36 Tolvaptan at all doses studied was associated with significant reductions in body weight and improvement in the signs and symptoms of heart failure. All doses were also associated with an increase in serum sodium levels in this study. Patients who were hyponatremic made up 28% of the study population and these patients experienced the greatest increase in serum sodium. Of note was the fact that as early as day 1 in the study 80% of tolvaptan (as opposed to 40% of placebo) patients had normalization of their serum sodium levels. These effects occurred without significant changes in blood pressure or renal function and the major side effects that were seen were polyuria, dry mouth, and thirst. This study was followed by the ACTIV in CHF trial which included a slightly larger population of 319 patients (of whom 21.3% were hyponatremic at baseline) who were hospitalized due to decompensated heart failure.17 Mean body weight decreased significantly more in patients treated with tolvaptan compared to those who received placebo. Tolvaptan‐treated patients also experienced increases in serum sodium that were greatest in the patients who were hyponatremic at baseline. These changes persisted throughout the duration of the study. On post hoc analysis, event‐free survival tended to be longer for the combined group of patients treated with tolvaptan compared to placebo but there were no differences in the rate of rehospitalization or unscheduled visits for heart failure. As in the initial study, tolvaptan was well tolerated, with dry mouth being the main side effect. There were no significant hemodynamic or renal effects.

The efficacy of vasopressin antagonism in heart failure outcome study with tolvaptan (EVEREST) study randomized 4133 patients hospitalized for decompensated heart failure to receive either tolvaptan 30 mg daily or placebo in addition to their standard therapy. The short‐term goal of the study was to assess the effects of therapy on a composite end‐point of patient assessed global clinical features and weight loss on day 7 (or at the time of hospital discharge) after starting treatment.37 The results of EVEREST demonstrated that patients treated with tolvaptan had greater improvement in the composite primary end‐point. This effect was driven by a greater reduction in body weight with active drug. Although, changes in global clinical status did not differ between the study groups, tolvaptan‐treated patients reported significantly greater improvement in dyspnea at day 1. In 1 (but not the other of the 2 component trials of EVEREST) there was also an improvement in edema. At day 1 and at discharge, the tolvaptan group with hyponatremia (defined as a serum sodium below 134 mEq/L) demonstrated significantly greater increases in serum sodium than in the hyponatremic placebo treated patients. Tolvaptan was well tolerated and serious adverse event frequencies were similar between groups, without excess renal failure or hypotension.

Patients who were enrolled in EVEREST were then followed for an average of 9.9 months on tolvaptan or placebo in order to assess the effects of treatment on the dual primary endpoints of all‐cause mortality (both superiority and noninferiority) and CV death or heart failure hospitalization.38 The results demonstrated no significant differences in either primary or secondary morbidity and mortality outcomes between tolvaptan and placebo treated patients. In the EVEREST patients with baseline serum sodium levels less than 134 mEq/L, there was a significant increase of 5.49 mEq/L 5.77 mEq/L (mean SD) at day 7 or discharge, if earlier, with tolvaptan, compared with 1.85 mEq/L 5.10 mEq/L in the placebo group. This effect was observed as early as day 1 and was maintained throughout the 40 weeks of treatment. Side effects were minimal. Overall, tolvaptan increased thirst and dry mouth, but the frequencies of major adverse events were similar in the 2 groups.

Two parallel multicenter, randomized, double‐blind, placebo‐controlled trials, termed collectively the Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2 (SALT‐1 and SALT‐2), examined the effect of tolvaptan on hypervolemic and euvolemic hyponatremia of diverse causes.39 The 448 patients included in the 2 studies were randomly assigned to either placebo or tolvaptan starting at a dose of 15 mg daily (increasing to 30 mg and then 60 mg if needed, depending on serum sodium concentrations) and followed over a 30 day period. The population included 138 patients (31%) with chronic heart failure as the cause of hyponatremia with the remainder of the population divided between patients with cirrhosis or syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH) and other causes of hyponatremia. The 2 primary end points for all patients were the change in the average daily area under the curve for the serum sodium concentration from baseline to day 4 and the change from baseline to day 30. As shown in Figure 3, serum sodium concentrations increased significantly more in the tolvaptan group than in the placebo group during the first 4 days and after the full 30 days of therapy. A planned analysis of the SALT trials demonstrated that correction of hyponatremia with tolvaptan was associated with significant improvement in self‐reported mental status, particularly in patients with marked hyponatremia or SIADH. Improvements in mental health scores were positively correlated with changes in serum [Na+] in both the tolvaptan and placebo groups and reversed after cessation of therapy, suggeting that hyponatremia‐associated impairments in mental function can be significantly improved by raising the serum [Na+]. The major side effects with tolvaptan included increased thirst, dry mouth, and increased urination. Tolvaptan has been approved by the US Food and Drug Administration (FDA) for the treatment of euvolemic and hypervolemic hyponatremia.

Figure 3

Lixivaptan is another selective V2 receptor antagonist that has been studied in heart failure patients.40 In a randomized, double‐blind, placebo‐controlled, ascending single‐dose study 42 diuretic‐requiring patients with mild‐to‐moderate heart failure patients received either placebo or doses of lixivaptan ranging from 10 mg to 400 mg. Except for patients who received the 10‐mg dose, lixivaptan produced a significant and dose‐related increase in urine volume over a 4‐hour period compared with placebo. Over 24 hours increases in urine volume were greater with lixivaptan than with placebo and these increases were accompanied by significant increases in solute‐free water excretion. At higher doses of lixivaptan, serum sodium levels increased significantly. The drug was tolerated in these patients and side effects tended to be mild. The Treatment of Hyponatremia Based on Lixivaptan in NYHA Class III/IV Cardiac Patient Evaluation (BALANCE Study) is an on‐going trial that is designed to evaluate whether lixivaptan is an effective and safe agent for increasing serum sodium in heart failure patients who are volume overloaded and have hyponatremia. The secondary end‐points of the BALANCE study include all‐cause mortality, CV effects, HF hospitalization and acute change in body weight.

The combined V1A and V2 receptor antagonist conivaptan has been approved by the FDA for the treatment of euvolemic and hypervolemic hyponatremia. The acute hemodynamic effects were studied in 142 NYHA class III and IV heart failure patients. Administration of 20 mg or 40 mg of conivaptan significantly reduced pulmonary artery wedge and right atrial pressures during the 3‐hour to 6‐hour interval after intravenous administration and significantly increased urine output in a dose‐dependent manner during the first 4 hours after the dose.41 In another study 170 patients hospitalized for worsening heart failure were randomly assigned to treatment with conivaptan (20‐mg loading dose followed by 2 successive 24‐hour continuous infusions of 40, 80, or 120 mg/day) or placebo in addition to their standard therapy.42 At 24 hours each dose of conivaptan had increased urine output significantly more than placebo with the difference averaging 1.0 to 1.5 L. The mean increase in serum sodium at 24, 48, and 72 hours was significantly higher in each of the conivaptan groups compared with the placebo group. At 48 hours, conivaptan increased serum sodium by 2.25 mmol/L to 3.27 mmol/L more than placebo. Conivaptan was well tolerated in these hospitalized heart failure patients. Infusion‐site reactions for this drug which is given intravenously were the most common adverse event and administration of the drug was not associated with clinically important changes in vital signs, electrolyte disturbances, or cardiac rhythm.

The effects of conivaptan on serum sodium levels were evaluated in 84 hospitalized patients with euvolemic or hypervolemic hyponatremia defined as a serum sodium between 115 mEq/ to 129 mEq/L.43 These patients received either intravenous placebo or conivaptan administered as a 30‐minute, 20‐mg loading dose followed by a 96‐hour infusion of either 40 mg/day or 80 mg/day. The results which are depicted in Figure 4 show that both conivaptan doses were associated with highly significant increases under the sodium‐time curve during the 4‐day treatment. From baseline to the end of treatment, serum sodium increased by 0.8 0.8 mEq/L with placebo as compared to 6.3 0.7 mEq/L and 9.4 0.8 mEq/L with the 40 mg and 80 mg doses of conivaptan. Conivaptan was generally well tolerated, although infusion‐site reactions led to the withdrawal of 1 (3%) and 4 (15%) of patients given conivaptan 40 mg/day and 80 mg/day, respectively.

Figure 4

The overall safety profile of the vaptans has been good. Most of the adverse effects including thirst, dry mouth and others have been minor and these agents, in general, have only minimal effects on blood pressure and renal function. In addition, the long‐term safety and tolerability of tolvaptan was demonstrated in the EVEREST trial. One theoretical concern about the use of vaptans to treat hyponatremia is that rapid correction of hyponatremia at a rate of >12 mEq/L over 24 hours can cause osmotic demyelination of brain structures with severe neurologic consequences. It has been advised that in susceptible patients (including those with severe malnutrition, alcoholism, or advanced liver disease) that sodium levels be corrected at a lower rate. It is also recommended that the drugs be initiated in hospital and that serum sodium is monitored during treatment.

Conclusions

Hyponatremia is common in heart failure patients, particularly during periods of decompensation. The presence of hyponatremia has been associated with a substantial increase in risk for longer hospitalization stay and mortality both in the hospital and following discharge. Hyponatremia has also been associated with alterations in cognitive and neuromuscular function which could further impair heart failure patients, particularly those who are elderly. The use of AVP receptor antagonists to treat hyponatremia is based on evidence that this peptide which regulates the flow of free water in the distal portion of the nephron is inappropriately elevated in heart failure patients. Administration of AVP receptor antagonists has been shown to increase and improve free water excretion and increase serum sodium levels in both euvolemic and volume overloaded hyponatremic patients. In addition to their favorable effects on serum sodium levels, the AVP receptor blockers have been shown to improve hemodynamics acutely and to increase weight loss in heart failure patients. There is some evidence that they also improve symptoms in hospitalized patients and that correction of hyponatremia is associated with improved cognitive and neuromuscular function. Currently available evidence, however, does not support a beneficial effect on long‐term outcomes such as mortality or CV hospitalizations. Additional on‐going clinical trials will provide further insights into this critical question. The overall side effect profile of the vaptans is favorable and published studies document the long‐term safety of administration of tolvaptan in heart failure patients. Thus, these agents represent an important new approach for treating hyponatremia in heart failure patients. They deserve consideration for use when hyponatremia is present during an episode of decompensated heart failure.

The scope and importance of communication between clinicians in the delivery of health care is increasingly being recognized.1, 2 Poor communication is known to be a source of inefficiency and errors within healthcare.36 The major issues with communication include the frequent use of interruptive communication mechanisms and the difficulty of knowing who to contact.2 Traditional paging remains the primary method to contact a physician despite being disruptive, inefficient, and predisposing to errors.710 The identification of the responsible physician for a patient can also be complicated with the numerous call schedules, different coverage rules, vacations, and protected academic time for residents. In 1 observational study, 25% of calls in a hospital were attempts to identify a responsible individual for a specific role.11 A recent study revealed that 14% of pages went to the wrong physician and that 47% of these errant pages warranted an urgent response.12 In our institution, the process for a nurse to identify which physician to contact regarding a patient care issue can be complex (Figure 1).

Figure 1

The use of email and mobile phone technology has been recommended as a method to improve communication.2 It can improve communication between clinicians by providing a method of triaging based on importance: instantly by telephone for urgent issues and less disruptively by email for nonurgent issues. There is limited literature on the use of email for improving communication between clinicians or on the use of smartphones. In a previous pilot study, we found that with minimal training, residents were able to use smartphones on general medical wards for clinical communication and that technical challenges were minimal.13 In an intensive care setting, the use of wireless emails using smartphones was perceived by staff to improve communication.14

Methods

Program Description

Recognizing the difficulty in implementing complex interventions within clinical care, we used a staged approach applying the standard Plan‐Do‐Study‐Act (PDSA) methodology for quality improvement.15 This involved developing a component of the system, releasing it to the users to learn from their experience, then taking this feedback to make changes and continuing with the next cycle. This allowed early identification and quicker resolution of issues.

Smartphones as Clinical Communication Tools

The first change implemented was to supplement the standard numeric pager with smartphones as the primary communication device for the residents. The BlackBerry device (Research in Motion, Ontario, Canada) was selected because it is an efficient, usable device with voice and secure email functionality that also happens to be the standard smartphone for our hospital administrators. Beginning in March 2008, all residents on the internal medicine service were equipped with a smartphone that they kept for their entire rotation. Contact lists of all devices were prepopulated with the hospital phone numbers that were important in coordinating patient care. These included numbers such as hospital flow coordinators, radiology reporting rooms, interventional radiology, and microbiology.

To facilitate reaching the most responsible resident for patients, we provided an additional smartphone, the Team BlackBerry, that was carried by the senior resident of each team during regular hours and then passed to the resident that was covering the team at night and on weekends. With the new process, a nurse would only require knowledge of which team the patient belonged to in order to contact the most responsible resident (Figure 2). The Team BlackBerry also received critical laboratory and medication alerts that contained clinical decision support. The laboratory and medication alerts were generated through the hospital rule‐based clinical decision support system (Misys Insight).

Figure 2

Web‐paging to Improve Nurse‐Physician Communication

In May 2008, we implemented a platform for text paging that we called web‐paging that allowed the nurses to efficiently send email messages securely through a hospital intranet page to the Team BlackBerry. A nurse would access the form from any computer on the wards, select the appropriate team, provide relevant information, and then send the message. Although the form would send an email, the term web‐paging was used to create familiarity with their previous process of contacting a resident, namely paging. This process reserved voice communication for urgent matters only while routing less urgent issues through the web‐paging form. Furthermore, emails were categorized into three priority levels:

• 1

  Call back requested messages were for issues that were not life threatening but needed immediate action or required discussion with a physician.

• 2

  E‐mail response requested messages were for issues that needed an action but could wait until the physician was available, such as cosigning an order.

• 3

  Information only with no response necessary messages facilitated 1‐way communication, such as updating the team of recent vital signs for a patient.

Physicians would receive prompt notification of a new email on their smartphone, and they could reply to the email or call back using a link within the email. Nurses were able to view the physician's email responses from an email account that was shared amongst the nurses on each ward.

Results

Discussion

The scope and importance of communication between clinicians in the delivery of health care is increasingly being recognized.1, 2 Poor communication is known to be a source of inefficiency and errors within healthcare.36 The major issues with communication include the frequent use of interruptive communication mechanisms and the difficulty of knowing who to contact.2 Traditional paging remains the primary method to contact a physician despite being disruptive, inefficient, and predisposing to errors.710 The identification of the responsible physician for a patient can also be complicated with the numerous call schedules, different coverage rules, vacations, and protected academic time for residents. In 1 observational study, 25% of calls in a hospital were attempts to identify a responsible individual for a specific role.11 A recent study revealed that 14% of pages went to the wrong physician and that 47% of these errant pages warranted an urgent response.12 In our institution, the process for a nurse to identify which physician to contact regarding a patient care issue can be complex (Figure 1).

Figure 1

The use of email and mobile phone technology has been recommended as a method to improve communication.2 It can improve communication between clinicians by providing a method of triaging based on importance: instantly by telephone for urgent issues and less disruptively by email for nonurgent issues. There is limited literature on the use of email for improving communication between clinicians or on the use of smartphones. In a previous pilot study, we found that with minimal training, residents were able to use smartphones on general medical wards for clinical communication and that technical challenges were minimal.13 In an intensive care setting, the use of wireless emails using smartphones was perceived by staff to improve communication.14

Methods

Program Description

Recognizing the difficulty in implementing complex interventions within clinical care, we used a staged approach applying the standard Plan‐Do‐Study‐Act (PDSA) methodology for quality improvement.15 This involved developing a component of the system, releasing it to the users to learn from their experience, then taking this feedback to make changes and continuing with the next cycle. This allowed early identification and quicker resolution of issues.

Smartphones as Clinical Communication Tools

The first change implemented was to supplement the standard numeric pager with smartphones as the primary communication device for the residents. The BlackBerry device (Research in Motion, Ontario, Canada) was selected because it is an efficient, usable device with voice and secure email functionality that also happens to be the standard smartphone for our hospital administrators. Beginning in March 2008, all residents on the internal medicine service were equipped with a smartphone that they kept for their entire rotation. Contact lists of all devices were prepopulated with the hospital phone numbers that were important in coordinating patient care. These included numbers such as hospital flow coordinators, radiology reporting rooms, interventional radiology, and microbiology.

To facilitate reaching the most responsible resident for patients, we provided an additional smartphone, the Team BlackBerry, that was carried by the senior resident of each team during regular hours and then passed to the resident that was covering the team at night and on weekends. With the new process, a nurse would only require knowledge of which team the patient belonged to in order to contact the most responsible resident (Figure 2). The Team BlackBerry also received critical laboratory and medication alerts that contained clinical decision support. The laboratory and medication alerts were generated through the hospital rule‐based clinical decision support system (Misys Insight).

Figure 2

Web‐paging to Improve Nurse‐Physician Communication

In May 2008, we implemented a platform for text paging that we called web‐paging that allowed the nurses to efficiently send email messages securely through a hospital intranet page to the Team BlackBerry. A nurse would access the form from any computer on the wards, select the appropriate team, provide relevant information, and then send the message. Although the form would send an email, the term web‐paging was used to create familiarity with their previous process of contacting a resident, namely paging. This process reserved voice communication for urgent matters only while routing less urgent issues through the web‐paging form. Furthermore, emails were categorized into three priority levels:

• 1

  Call back requested messages were for issues that were not life threatening but needed immediate action or required discussion with a physician.

• 2

  E‐mail response requested messages were for issues that needed an action but could wait until the physician was available, such as cosigning an order.

• 3

  Information only with no response necessary messages facilitated 1‐way communication, such as updating the team of recent vital signs for a patient.

Physicians would receive prompt notification of a new email on their smartphone, and they could reply to the email or call back using a link within the email. Nurses were able to view the physician's email responses from an email account that was shared amongst the nurses on each ward.

Results

Discussion

The scope and importance of communication between clinicians in the delivery of health care is increasingly being recognized.1, 2 Poor communication is known to be a source of inefficiency and errors within healthcare.36 The major issues with communication include the frequent use of interruptive communication mechanisms and the difficulty of knowing who to contact.2 Traditional paging remains the primary method to contact a physician despite being disruptive, inefficient, and predisposing to errors.710 The identification of the responsible physician for a patient can also be complicated with the numerous call schedules, different coverage rules, vacations, and protected academic time for residents. In 1 observational study, 25% of calls in a hospital were attempts to identify a responsible individual for a specific role.11 A recent study revealed that 14% of pages went to the wrong physician and that 47% of these errant pages warranted an urgent response.12 In our institution, the process for a nurse to identify which physician to contact regarding a patient care issue can be complex (Figure 1).

Figure 1

The use of email and mobile phone technology has been recommended as a method to improve communication.2 It can improve communication between clinicians by providing a method of triaging based on importance: instantly by telephone for urgent issues and less disruptively by email for nonurgent issues. There is limited literature on the use of email for improving communication between clinicians or on the use of smartphones. In a previous pilot study, we found that with minimal training, residents were able to use smartphones on general medical wards for clinical communication and that technical challenges were minimal.13 In an intensive care setting, the use of wireless emails using smartphones was perceived by staff to improve communication.14

Methods

Program Description

Recognizing the difficulty in implementing complex interventions within clinical care, we used a staged approach applying the standard Plan‐Do‐Study‐Act (PDSA) methodology for quality improvement.15 This involved developing a component of the system, releasing it to the users to learn from their experience, then taking this feedback to make changes and continuing with the next cycle. This allowed early identification and quicker resolution of issues.

Smartphones as Clinical Communication Tools

The first change implemented was to supplement the standard numeric pager with smartphones as the primary communication device for the residents. The BlackBerry device (Research in Motion, Ontario, Canada) was selected because it is an efficient, usable device with voice and secure email functionality that also happens to be the standard smartphone for our hospital administrators. Beginning in March 2008, all residents on the internal medicine service were equipped with a smartphone that they kept for their entire rotation. Contact lists of all devices were prepopulated with the hospital phone numbers that were important in coordinating patient care. These included numbers such as hospital flow coordinators, radiology reporting rooms, interventional radiology, and microbiology.

To facilitate reaching the most responsible resident for patients, we provided an additional smartphone, the Team BlackBerry, that was carried by the senior resident of each team during regular hours and then passed to the resident that was covering the team at night and on weekends. With the new process, a nurse would only require knowledge of which team the patient belonged to in order to contact the most responsible resident (Figure 2). The Team BlackBerry also received critical laboratory and medication alerts that contained clinical decision support. The laboratory and medication alerts were generated through the hospital rule‐based clinical decision support system (Misys Insight).

Figure 2

Web‐paging to Improve Nurse‐Physician Communication

In May 2008, we implemented a platform for text paging that we called web‐paging that allowed the nurses to efficiently send email messages securely through a hospital intranet page to the Team BlackBerry. A nurse would access the form from any computer on the wards, select the appropriate team, provide relevant information, and then send the message. Although the form would send an email, the term web‐paging was used to create familiarity with their previous process of contacting a resident, namely paging. This process reserved voice communication for urgent matters only while routing less urgent issues through the web‐paging form. Furthermore, emails were categorized into three priority levels:

• 1

  Call back requested messages were for issues that were not life threatening but needed immediate action or required discussion with a physician.

• 2

  E‐mail response requested messages were for issues that needed an action but could wait until the physician was available, such as cosigning an order.

• 3

  Information only with no response necessary messages facilitated 1‐way communication, such as updating the team of recent vital signs for a patient.

Physicians would receive prompt notification of a new email on their smartphone, and they could reply to the email or call back using a link within the email. Nurses were able to view the physician's email responses from an email account that was shared amongst the nurses on each ward.

Results

Discussion

Hyperglycemia is common in hospitalized patients, and hyperglycemia has been associated with poor hospital outcomes. The adverse physiologic effects of acute hyperglycemia are well established1 and several clinical studies have linked hyperglycemia with poor clinical outcomes in certain patient populations.28 Although the optimal target range for inpatient glycemic control has not yet been defined, these studies support the goal of metabolic control for hospital patients. However, there are many barriers to achieving adequate glycemic control in the hospital, and blood glucoses in the hospital are often far from recommended targets.9, 10 One barrier appears to be the low priority given to glycemic control in the hospital. Hyperglycemia in the hospital is often ignored,11 and insulin regimens are often chosen for simplicity as opposed to effectiveness.12 Other barriers to glycemic control in the hospital include the physiologic effects (stress) of acute illness, and the frequent nutritional changes and interruptions that occur.

Most hyperglycemic patients on a general medicine unit are treated with subcutaneous insulin, but the optimal strategy for prescribing insulin in the hospital remains uncertain. A technical review of the literature on the management of diabetes in the hospital setting from 2004 recommends prescribing insulin in a way that mimics physiologic insulin secretion (ie, physiologic or basal‐bolus insulin).1 This approach has been promulgated by experts, but there has been very little research to support these recommendations. One small, randomized trial concluded that a basal‐bolus approach achieved better glycemic control than the use of sliding‐scale insulin alone,13 and 2 quality improvement studies using a before/after design have demonstrated improvements in glycemic control after the implementation of interventions designed to encourage physiologic insulin use.14, 15

In this study we hypothesized that a few simple interventions (education for physicians and nurses, and a standardized insulin order form) would lead to a higher rate of basal‐bolus insulin use and simultaneously improve glycemic control and patient safety.

Methods

Results

A total of 245 patients provided 1315 patient‐days. Patient demographics are shown in Table 2. The patients' weight, length‐of‐stay, and primary diagnoses were similar across the 3 groups. There was a higher percentage of males in the IG as compared to the HCG.

Table 3 shows the insulin regimens used in the different groups. The use of basal insulin was similar between groups. Congruent with the goals of the education session and the order set, patients in the IG were more likely to be treated with a combination of basal and nutritional insulin than patients in the other groups. Patients in the HCG were more likely to be treated with a premixed insulin than patients in the other groups. However, even when premixed insulin was categorized as a form of basal plus nutritional insulin and combined into a composite group with the combined basal and nutritional days, this type of regimen remained more common in the IG than in the HCG. The rate of sliding scale insulin use alone (ie, without any scheduled insulin) was similar in the 3 groups.

Other relevant measures are also shown in Table 3. The use of oral diabetes agents was similar in the 3 groups. The use of a nonoral feeding route (eg, tube feeding or parenteral nutrition) was infrequent.

A comparison of glycemic control in the three groups is shown in Table 4. In contrast to the CCG, patients in the IG experienced more days within the target glucose range (17% vs. 10.6%, P < 0.01), fewer days with severe hyperglycemia (48.3% vs. 59.2%, P < 0.01), and had a lower day‐weighted average blood glucose (195.9 vs. 212.6, P < 0.01). Compared to the HCG, patients in the IG experienced similar rates of hyperglycemia, but fewer hypoglycemic days (5.1% vs. 9.2%, P = 0.02).

The percentages of patients with severe hyperglycemia in each group are shown in Figure 1 by hospital day. Severe hyperglycemia was common, but there was a trend towards a decrease in the prevalence of severe hyperglycemia with increasing hospital days for all study groups, although it was consistently higher in the CCG than in the IG. Figure 2 shows the types of insulin regimens used by hospital day (composite for all groups). The use of basal plus nutritional insulin (the recommended regimen) increased gradually with increasing hospital days. When taken together, the information in both figures support the hypothesis that the use of the recommended insulin regimen may have contributed to the modest improvements in glycemic control seen in the IG.

Figure 1

Figure 2

In the final adjusted regression model, the intervention had a positive impact on glycemic control (Table 5). Subjects in the IG had a 72% increase in the odds of being in the target glucose range when compared to subjects in the CCG (P = 0.01). In addition, subjects in the IG had a 35% reduction in the odds of being severely hyperglycemic when compared to those in the CCG (P < 0.01). Finally, the odds ratio (OR) for being hypoglycemic among intervention subjects was 0.59 (P = 0.06) when compared to subjects in the CCG and 0.48 (P = 0.01) when compared to subjects in the HCG.

Discussion

In this study, we investigated the effects of a standardized insulin order set, coupled with physician and nurse education, on glycemic control in hyperglycemic hospitalized patients. These interventions were designed to encourage a standardized approach to the treatment of hyperglycemia in hospitalized patients, based on the principles of physiologic insulin use, as described above. Our data suggest that the interventions did, indeed, alter the way insulin was prescribed, as more patients in the IG received a combination of basal plus nutritional insulin (the recommended regimen) than in the other groups. These interventions were associated with improved glycemic outcomes in the IG as compared to the CCG. The IG experienced a higher percentage of days in the target range and a trend toward fewer hypoglycemic days than the CCG. Although the IG experienced a similar percentage of days in the target range, it had significantly fewer hypoglycemic days than the HCG.

It is useful to consider the results of our study in the context of 2 other similar studies performed by Schnipper et al.14 and Maynard et al.15 Although each of these 3 studies have different study designs, they are similar in intent (to test the effects of simple quality improvement interventions on glycemic control in the hospital) and results (all showed significant improvements in some aspect of glycemic control). In our study, and the study by Maynard et al.,15 the interventions also led to decreases in the rates of hypoglycemia, whereas Schnipper et al.14 observed no difference in hypoglycemia. Of interest, in each of the three studies the interventions were associated with an increase in the use of some type of scheduled insulin. In our study and the study from Schnipper et al.14 the baseline use of basal insulin was quite high, and the interventions were associated with a significant increase in the addition of nutritional insulin. In the Maynard et al.15 study, the baseline use of sliding scale insulin alone was prevalent, and the interventions resulted in an increase in the use of basal insulin. The results of these studies, taken together, prompt us to conclude that the interventions employed in these studies are likely to lead to more frequent prescription of scheduled (anticipatory) insulin, and a modest improvement in glycemic control, without an increase (and perhaps with a decrease) in hypoglycemia.

A few of our study results are unexpected, or difficult to explain. In contrast to the other studies discussed above, our interventions did not affect the frequency of the use of sliding‐scale insulin alone (without any scheduled insulin), which was similar in the 3 groups. Although the reason for this is uncertain, we hypothesize that the high baseline use of basal insulin in our institution, and the lack of a hard stop preventing the use of sliding scale insulin alone explain this finding. Also, it is difficult to explain why measures of hyperglycemia were similar between the IG and the HCG despite the fact that the HCG was less often treated with a combination of basal and nutritional insulin and more often treated with mixed insulin.

There are several different mechanisms by which the interventions might have resulted in improved glycemic control in the IG compared to CCG. Our data clearly shows that insulin was prescribed differently in the IG, and the more frequent use of a combination of scheduled basal and nutritional insulin might have contributed to the differences between the groups. However, the effects of our interventions clearly went beyond physician education into the realm of true process improvement and standardization. The standardized order form was designed to prompt physicians to use a basal‐bolus insulin regimen. The order form also created nursing expectations of how insulin should be ordered, and clarified the roles of the different insulins that were prescribed.

On the medication administration record, each insulin was labeled as basal insulin (to be given even when fasting) or nutritional insulin (to be given along with the meal). The nurses caring for the IG also attended an education program that reinforced the role of the nurse in the bedside management of insulin administration. Specifically, nurses were taught to assess the premeal blood glucose and the patient's nutritional situation before giving the nutritional insulin (ie, Does the patient have food available? Will he tolerate eating the food?). In situations where is was not clear if the patient would be able to tolerate the ordered nutrition, the order set empowered the nurse to give the nutritional insulin after the meal, and to reduce the dose to match the patient's actual intake. These interventions resulted in some fundamental improvements in the nursing process of delivering insulin to the patient, and these changes might have resulted in improvements via mechanisms that are difficult to directly measure. Since the same physicians cared for both the IG and the CCG, interventions other than physician education clearly contributed to the observed improvements in the IG.

This study was not a randomized study, and there could be important undetected differences between the groups. However, all of the patients were admitted to the General Medicine Inpatient Services and the comparison of the general patient demographics and primary diagnoses between the groups do not suggest major differences.

Although the improvements in glycemic control seen in this study were statistically significant, they were quantitatively modest. The rates of hyperglycemia seen in this study, on the other hand, are quite remarkable. Both the American Diabetes Association and the American College of Endocrinology have recommended that blood glucoses in hospitalized patients not exceed a maximum value of 180 mg/dL, but the day‐weighted average blood glucose in this study was above that for each group. Even in the IG, over 80% of all patient‐days included at least 1 blood glucose value outside of the target range. These data suggest that better strategies for achieving metabolic control in hospitalized patients are needed.

It is worth mentioning that our interventions were not aggressively enforced. While the use of the order set was mandatory for the IG, it was flexible enough to allow for substantial practice variation, especially with respect to the dose of insulin prescribed. Although the education sessions discussed the specifics of insulin dosing in hospitalized patients, the order form did not offer dosing guidelines. It is possible that our interventions may have had a larger impact if a starting dose of insulin had been specified on the form. Although the insulin order form prompted physicians to act, there were no forced functions. Also, not all house staff attended the education sessions for physicians, and there was no feedback provided to physicians related to how they might improve their adherence to the recommendations presented in the educational module. Therefore, it is likely that more aggressive interventions could have led to greater changes in physician practice.

In conclusion, this study demonstrates that interventions including physician and nurse education and a standardized insulin order set can lead to improvement in glycemic control and patient safety in hospitalized patients treated with subcutaneous insulin. However, the observed improvements are modest, and poor metabolic control remains common, despite these interventions. These data suggest that standardization of the process of ordering and delivering subcutaneous insulin in the hospital may lead to a reduction in both hyperglycemia and hypoglycemia. However, it is clear that the interventions used in this study were not potent enough to achieve the recommended glycemic targets for the majority of patients. Additional research is needed to determine the best strategy for achieving safe and effective metabolic control in hospitalized, hyperglycemic, noncritically ill patients.

Hyperglycemia is common in hospitalized patients, and hyperglycemia has been associated with poor hospital outcomes. The adverse physiologic effects of acute hyperglycemia are well established1 and several clinical studies have linked hyperglycemia with poor clinical outcomes in certain patient populations.28 Although the optimal target range for inpatient glycemic control has not yet been defined, these studies support the goal of metabolic control for hospital patients. However, there are many barriers to achieving adequate glycemic control in the hospital, and blood glucoses in the hospital are often far from recommended targets.9, 10 One barrier appears to be the low priority given to glycemic control in the hospital. Hyperglycemia in the hospital is often ignored,11 and insulin regimens are often chosen for simplicity as opposed to effectiveness.12 Other barriers to glycemic control in the hospital include the physiologic effects (stress) of acute illness, and the frequent nutritional changes and interruptions that occur.

Most hyperglycemic patients on a general medicine unit are treated with subcutaneous insulin, but the optimal strategy for prescribing insulin in the hospital remains uncertain. A technical review of the literature on the management of diabetes in the hospital setting from 2004 recommends prescribing insulin in a way that mimics physiologic insulin secretion (ie, physiologic or basal‐bolus insulin).1 This approach has been promulgated by experts, but there has been very little research to support these recommendations. One small, randomized trial concluded that a basal‐bolus approach achieved better glycemic control than the use of sliding‐scale insulin alone,13 and 2 quality improvement studies using a before/after design have demonstrated improvements in glycemic control after the implementation of interventions designed to encourage physiologic insulin use.14, 15

In this study we hypothesized that a few simple interventions (education for physicians and nurses, and a standardized insulin order form) would lead to a higher rate of basal‐bolus insulin use and simultaneously improve glycemic control and patient safety.

Methods

Results

A total of 245 patients provided 1315 patient‐days. Patient demographics are shown in Table 2. The patients' weight, length‐of‐stay, and primary diagnoses were similar across the 3 groups. There was a higher percentage of males in the IG as compared to the HCG.

Table 3 shows the insulin regimens used in the different groups. The use of basal insulin was similar between groups. Congruent with the goals of the education session and the order set, patients in the IG were more likely to be treated with a combination of basal and nutritional insulin than patients in the other groups. Patients in the HCG were more likely to be treated with a premixed insulin than patients in the other groups. However, even when premixed insulin was categorized as a form of basal plus nutritional insulin and combined into a composite group with the combined basal and nutritional days, this type of regimen remained more common in the IG than in the HCG. The rate of sliding scale insulin use alone (ie, without any scheduled insulin) was similar in the 3 groups.

Other relevant measures are also shown in Table 3. The use of oral diabetes agents was similar in the 3 groups. The use of a nonoral feeding route (eg, tube feeding or parenteral nutrition) was infrequent.

A comparison of glycemic control in the three groups is shown in Table 4. In contrast to the CCG, patients in the IG experienced more days within the target glucose range (17% vs. 10.6%, P < 0.01), fewer days with severe hyperglycemia (48.3% vs. 59.2%, P < 0.01), and had a lower day‐weighted average blood glucose (195.9 vs. 212.6, P < 0.01). Compared to the HCG, patients in the IG experienced similar rates of hyperglycemia, but fewer hypoglycemic days (5.1% vs. 9.2%, P = 0.02).

The percentages of patients with severe hyperglycemia in each group are shown in Figure 1 by hospital day. Severe hyperglycemia was common, but there was a trend towards a decrease in the prevalence of severe hyperglycemia with increasing hospital days for all study groups, although it was consistently higher in the CCG than in the IG. Figure 2 shows the types of insulin regimens used by hospital day (composite for all groups). The use of basal plus nutritional insulin (the recommended regimen) increased gradually with increasing hospital days. When taken together, the information in both figures support the hypothesis that the use of the recommended insulin regimen may have contributed to the modest improvements in glycemic control seen in the IG.

Figure 1

Figure 2

In the final adjusted regression model, the intervention had a positive impact on glycemic control (Table 5). Subjects in the IG had a 72% increase in the odds of being in the target glucose range when compared to subjects in the CCG (P = 0.01). In addition, subjects in the IG had a 35% reduction in the odds of being severely hyperglycemic when compared to those in the CCG (P < 0.01). Finally, the odds ratio (OR) for being hypoglycemic among intervention subjects was 0.59 (P = 0.06) when compared to subjects in the CCG and 0.48 (P = 0.01) when compared to subjects in the HCG.

Discussion

In this study, we investigated the effects of a standardized insulin order set, coupled with physician and nurse education, on glycemic control in hyperglycemic hospitalized patients. These interventions were designed to encourage a standardized approach to the treatment of hyperglycemia in hospitalized patients, based on the principles of physiologic insulin use, as described above. Our data suggest that the interventions did, indeed, alter the way insulin was prescribed, as more patients in the IG received a combination of basal plus nutritional insulin (the recommended regimen) than in the other groups. These interventions were associated with improved glycemic outcomes in the IG as compared to the CCG. The IG experienced a higher percentage of days in the target range and a trend toward fewer hypoglycemic days than the CCG. Although the IG experienced a similar percentage of days in the target range, it had significantly fewer hypoglycemic days than the HCG.

It is useful to consider the results of our study in the context of 2 other similar studies performed by Schnipper et al.14 and Maynard et al.15 Although each of these 3 studies have different study designs, they are similar in intent (to test the effects of simple quality improvement interventions on glycemic control in the hospital) and results (all showed significant improvements in some aspect of glycemic control). In our study, and the study by Maynard et al.,15 the interventions also led to decreases in the rates of hypoglycemia, whereas Schnipper et al.14 observed no difference in hypoglycemia. Of interest, in each of the three studies the interventions were associated with an increase in the use of some type of scheduled insulin. In our study and the study from Schnipper et al.14 the baseline use of basal insulin was quite high, and the interventions were associated with a significant increase in the addition of nutritional insulin. In the Maynard et al.15 study, the baseline use of sliding scale insulin alone was prevalent, and the interventions resulted in an increase in the use of basal insulin. The results of these studies, taken together, prompt us to conclude that the interventions employed in these studies are likely to lead to more frequent prescription of scheduled (anticipatory) insulin, and a modest improvement in glycemic control, without an increase (and perhaps with a decrease) in hypoglycemia.

A few of our study results are unexpected, or difficult to explain. In contrast to the other studies discussed above, our interventions did not affect the frequency of the use of sliding‐scale insulin alone (without any scheduled insulin), which was similar in the 3 groups. Although the reason for this is uncertain, we hypothesize that the high baseline use of basal insulin in our institution, and the lack of a hard stop preventing the use of sliding scale insulin alone explain this finding. Also, it is difficult to explain why measures of hyperglycemia were similar between the IG and the HCG despite the fact that the HCG was less often treated with a combination of basal and nutritional insulin and more often treated with mixed insulin.

There are several different mechanisms by which the interventions might have resulted in improved glycemic control in the IG compared to CCG. Our data clearly shows that insulin was prescribed differently in the IG, and the more frequent use of a combination of scheduled basal and nutritional insulin might have contributed to the differences between the groups. However, the effects of our interventions clearly went beyond physician education into the realm of true process improvement and standardization. The standardized order form was designed to prompt physicians to use a basal‐bolus insulin regimen. The order form also created nursing expectations of how insulin should be ordered, and clarified the roles of the different insulins that were prescribed.

On the medication administration record, each insulin was labeled as basal insulin (to be given even when fasting) or nutritional insulin (to be given along with the meal). The nurses caring for the IG also attended an education program that reinforced the role of the nurse in the bedside management of insulin administration. Specifically, nurses were taught to assess the premeal blood glucose and the patient's nutritional situation before giving the nutritional insulin (ie, Does the patient have food available? Will he tolerate eating the food?). In situations where is was not clear if the patient would be able to tolerate the ordered nutrition, the order set empowered the nurse to give the nutritional insulin after the meal, and to reduce the dose to match the patient's actual intake. These interventions resulted in some fundamental improvements in the nursing process of delivering insulin to the patient, and these changes might have resulted in improvements via mechanisms that are difficult to directly measure. Since the same physicians cared for both the IG and the CCG, interventions other than physician education clearly contributed to the observed improvements in the IG.

This study was not a randomized study, and there could be important undetected differences between the groups. However, all of the patients were admitted to the General Medicine Inpatient Services and the comparison of the general patient demographics and primary diagnoses between the groups do not suggest major differences.

Although the improvements in glycemic control seen in this study were statistically significant, they were quantitatively modest. The rates of hyperglycemia seen in this study, on the other hand, are quite remarkable. Both the American Diabetes Association and the American College of Endocrinology have recommended that blood glucoses in hospitalized patients not exceed a maximum value of 180 mg/dL, but the day‐weighted average blood glucose in this study was above that for each group. Even in the IG, over 80% of all patient‐days included at least 1 blood glucose value outside of the target range. These data suggest that better strategies for achieving metabolic control in hospitalized patients are needed.

It is worth mentioning that our interventions were not aggressively enforced. While the use of the order set was mandatory for the IG, it was flexible enough to allow for substantial practice variation, especially with respect to the dose of insulin prescribed. Although the education sessions discussed the specifics of insulin dosing in hospitalized patients, the order form did not offer dosing guidelines. It is possible that our interventions may have had a larger impact if a starting dose of insulin had been specified on the form. Although the insulin order form prompted physicians to act, there were no forced functions. Also, not all house staff attended the education sessions for physicians, and there was no feedback provided to physicians related to how they might improve their adherence to the recommendations presented in the educational module. Therefore, it is likely that more aggressive interventions could have led to greater changes in physician practice.

In conclusion, this study demonstrates that interventions including physician and nurse education and a standardized insulin order set can lead to improvement in glycemic control and patient safety in hospitalized patients treated with subcutaneous insulin. However, the observed improvements are modest, and poor metabolic control remains common, despite these interventions. These data suggest that standardization of the process of ordering and delivering subcutaneous insulin in the hospital may lead to a reduction in both hyperglycemia and hypoglycemia. However, it is clear that the interventions used in this study were not potent enough to achieve the recommended glycemic targets for the majority of patients. Additional research is needed to determine the best strategy for achieving safe and effective metabolic control in hospitalized, hyperglycemic, noncritically ill patients.

Hyperglycemia is common in hospitalized patients, and hyperglycemia has been associated with poor hospital outcomes. The adverse physiologic effects of acute hyperglycemia are well established1 and several clinical studies have linked hyperglycemia with poor clinical outcomes in certain patient populations.28 Although the optimal target range for inpatient glycemic control has not yet been defined, these studies support the goal of metabolic control for hospital patients. However, there are many barriers to achieving adequate glycemic control in the hospital, and blood glucoses in the hospital are often far from recommended targets.9, 10 One barrier appears to be the low priority given to glycemic control in the hospital. Hyperglycemia in the hospital is often ignored,11 and insulin regimens are often chosen for simplicity as opposed to effectiveness.12 Other barriers to glycemic control in the hospital include the physiologic effects (stress) of acute illness, and the frequent nutritional changes and interruptions that occur.

Most hyperglycemic patients on a general medicine unit are treated with subcutaneous insulin, but the optimal strategy for prescribing insulin in the hospital remains uncertain. A technical review of the literature on the management of diabetes in the hospital setting from 2004 recommends prescribing insulin in a way that mimics physiologic insulin secretion (ie, physiologic or basal‐bolus insulin).1 This approach has been promulgated by experts, but there has been very little research to support these recommendations. One small, randomized trial concluded that a basal‐bolus approach achieved better glycemic control than the use of sliding‐scale insulin alone,13 and 2 quality improvement studies using a before/after design have demonstrated improvements in glycemic control after the implementation of interventions designed to encourage physiologic insulin use.14, 15

In this study we hypothesized that a few simple interventions (education for physicians and nurses, and a standardized insulin order form) would lead to a higher rate of basal‐bolus insulin use and simultaneously improve glycemic control and patient safety.

Methods

Results

A total of 245 patients provided 1315 patient‐days. Patient demographics are shown in Table 2. The patients' weight, length‐of‐stay, and primary diagnoses were similar across the 3 groups. There was a higher percentage of males in the IG as compared to the HCG.

Table 3 shows the insulin regimens used in the different groups. The use of basal insulin was similar between groups. Congruent with the goals of the education session and the order set, patients in the IG were more likely to be treated with a combination of basal and nutritional insulin than patients in the other groups. Patients in the HCG were more likely to be treated with a premixed insulin than patients in the other groups. However, even when premixed insulin was categorized as a form of basal plus nutritional insulin and combined into a composite group with the combined basal and nutritional days, this type of regimen remained more common in the IG than in the HCG. The rate of sliding scale insulin use alone (ie, without any scheduled insulin) was similar in the 3 groups.

Other relevant measures are also shown in Table 3. The use of oral diabetes agents was similar in the 3 groups. The use of a nonoral feeding route (eg, tube feeding or parenteral nutrition) was infrequent.

A comparison of glycemic control in the three groups is shown in Table 4. In contrast to the CCG, patients in the IG experienced more days within the target glucose range (17% vs. 10.6%, P < 0.01), fewer days with severe hyperglycemia (48.3% vs. 59.2%, P < 0.01), and had a lower day‐weighted average blood glucose (195.9 vs. 212.6, P < 0.01). Compared to the HCG, patients in the IG experienced similar rates of hyperglycemia, but fewer hypoglycemic days (5.1% vs. 9.2%, P = 0.02).

The percentages of patients with severe hyperglycemia in each group are shown in Figure 1 by hospital day. Severe hyperglycemia was common, but there was a trend towards a decrease in the prevalence of severe hyperglycemia with increasing hospital days for all study groups, although it was consistently higher in the CCG than in the IG. Figure 2 shows the types of insulin regimens used by hospital day (composite for all groups). The use of basal plus nutritional insulin (the recommended regimen) increased gradually with increasing hospital days. When taken together, the information in both figures support the hypothesis that the use of the recommended insulin regimen may have contributed to the modest improvements in glycemic control seen in the IG.

Figure 1

Figure 2

In the final adjusted regression model, the intervention had a positive impact on glycemic control (Table 5). Subjects in the IG had a 72% increase in the odds of being in the target glucose range when compared to subjects in the CCG (P = 0.01). In addition, subjects in the IG had a 35% reduction in the odds of being severely hyperglycemic when compared to those in the CCG (P < 0.01). Finally, the odds ratio (OR) for being hypoglycemic among intervention subjects was 0.59 (P = 0.06) when compared to subjects in the CCG and 0.48 (P = 0.01) when compared to subjects in the HCG.

Discussion

In this study, we investigated the effects of a standardized insulin order set, coupled with physician and nurse education, on glycemic control in hyperglycemic hospitalized patients. These interventions were designed to encourage a standardized approach to the treatment of hyperglycemia in hospitalized patients, based on the principles of physiologic insulin use, as described above. Our data suggest that the interventions did, indeed, alter the way insulin was prescribed, as more patients in the IG received a combination of basal plus nutritional insulin (the recommended regimen) than in the other groups. These interventions were associated with improved glycemic outcomes in the IG as compared to the CCG. The IG experienced a higher percentage of days in the target range and a trend toward fewer hypoglycemic days than the CCG. Although the IG experienced a similar percentage of days in the target range, it had significantly fewer hypoglycemic days than the HCG.

It is useful to consider the results of our study in the context of 2 other similar studies performed by Schnipper et al.14 and Maynard et al.15 Although each of these 3 studies have different study designs, they are similar in intent (to test the effects of simple quality improvement interventions on glycemic control in the hospital) and results (all showed significant improvements in some aspect of glycemic control). In our study, and the study by Maynard et al.,15 the interventions also led to decreases in the rates of hypoglycemia, whereas Schnipper et al.14 observed no difference in hypoglycemia. Of interest, in each of the three studies the interventions were associated with an increase in the use of some type of scheduled insulin. In our study and the study from Schnipper et al.14 the baseline use of basal insulin was quite high, and the interventions were associated with a significant increase in the addition of nutritional insulin. In the Maynard et al.15 study, the baseline use of sliding scale insulin alone was prevalent, and the interventions resulted in an increase in the use of basal insulin. The results of these studies, taken together, prompt us to conclude that the interventions employed in these studies are likely to lead to more frequent prescription of scheduled (anticipatory) insulin, and a modest improvement in glycemic control, without an increase (and perhaps with a decrease) in hypoglycemia.

A few of our study results are unexpected, or difficult to explain. In contrast to the other studies discussed above, our interventions did not affect the frequency of the use of sliding‐scale insulin alone (without any scheduled insulin), which was similar in the 3 groups. Although the reason for this is uncertain, we hypothesize that the high baseline use of basal insulin in our institution, and the lack of a hard stop preventing the use of sliding scale insulin alone explain this finding. Also, it is difficult to explain why measures of hyperglycemia were similar between the IG and the HCG despite the fact that the HCG was less often treated with a combination of basal and nutritional insulin and more often treated with mixed insulin.

There are several different mechanisms by which the interventions might have resulted in improved glycemic control in the IG compared to CCG. Our data clearly shows that insulin was prescribed differently in the IG, and the more frequent use of a combination of scheduled basal and nutritional insulin might have contributed to the differences between the groups. However, the effects of our interventions clearly went beyond physician education into the realm of true process improvement and standardization. The standardized order form was designed to prompt physicians to use a basal‐bolus insulin regimen. The order form also created nursing expectations of how insulin should be ordered, and clarified the roles of the different insulins that were prescribed.

On the medication administration record, each insulin was labeled as basal insulin (to be given even when fasting) or nutritional insulin (to be given along with the meal). The nurses caring for the IG also attended an education program that reinforced the role of the nurse in the bedside management of insulin administration. Specifically, nurses were taught to assess the premeal blood glucose and the patient's nutritional situation before giving the nutritional insulin (ie, Does the patient have food available? Will he tolerate eating the food?). In situations where is was not clear if the patient would be able to tolerate the ordered nutrition, the order set empowered the nurse to give the nutritional insulin after the meal, and to reduce the dose to match the patient's actual intake. These interventions resulted in some fundamental improvements in the nursing process of delivering insulin to the patient, and these changes might have resulted in improvements via mechanisms that are difficult to directly measure. Since the same physicians cared for both the IG and the CCG, interventions other than physician education clearly contributed to the observed improvements in the IG.

This study was not a randomized study, and there could be important undetected differences between the groups. However, all of the patients were admitted to the General Medicine Inpatient Services and the comparison of the general patient demographics and primary diagnoses between the groups do not suggest major differences.

Although the improvements in glycemic control seen in this study were statistically significant, they were quantitatively modest. The rates of hyperglycemia seen in this study, on the other hand, are quite remarkable. Both the American Diabetes Association and the American College of Endocrinology have recommended that blood glucoses in hospitalized patients not exceed a maximum value of 180 mg/dL, but the day‐weighted average blood glucose in this study was above that for each group. Even in the IG, over 80% of all patient‐days included at least 1 blood glucose value outside of the target range. These data suggest that better strategies for achieving metabolic control in hospitalized patients are needed.

It is worth mentioning that our interventions were not aggressively enforced. While the use of the order set was mandatory for the IG, it was flexible enough to allow for substantial practice variation, especially with respect to the dose of insulin prescribed. Although the education sessions discussed the specifics of insulin dosing in hospitalized patients, the order form did not offer dosing guidelines. It is possible that our interventions may have had a larger impact if a starting dose of insulin had been specified on the form. Although the insulin order form prompted physicians to act, there were no forced functions. Also, not all house staff attended the education sessions for physicians, and there was no feedback provided to physicians related to how they might improve their adherence to the recommendations presented in the educational module. Therefore, it is likely that more aggressive interventions could have led to greater changes in physician practice.

In conclusion, this study demonstrates that interventions including physician and nurse education and a standardized insulin order set can lead to improvement in glycemic control and patient safety in hospitalized patients treated with subcutaneous insulin. However, the observed improvements are modest, and poor metabolic control remains common, despite these interventions. These data suggest that standardization of the process of ordering and delivering subcutaneous insulin in the hospital may lead to a reduction in both hyperglycemia and hypoglycemia. However, it is clear that the interventions used in this study were not potent enough to achieve the recommended glycemic targets for the majority of patients. Additional research is needed to determine the best strategy for achieving safe and effective metabolic control in hospitalized, hyperglycemic, noncritically ill patients.