Osmolality vs Effective Osmolality
 Osmolality: total number of particles in an aqueous
solution (mosmol/kg H2O)
 Normal Posm = 275-290 mosmol/kg
 Effective osmolality (tonicity): those particles that can
exert osmotic force across membranes, via movement
of water into or out of cells
 Examples: Na+, glucose, mannitol
 Normal effective Posm = 270-285 mosmol/kg
Plasma Osmolality
 Na+, glucose and BUN are major determinants of
plasma osmolality
 Posm = 2 x plasma [Na+] + [Glucose]/18 + [BUN]/2.8
 More important clinically to consider effective
osmolality than “total’’ osmolality
 Effective osmoles (Na+ , glucose) exert water shifts
unlike urea (as well as ethanol)
Plasma Osmolality
Is hyponatremia always
associated with a low
plasma osmolality?
NO
Plasma Osmolality
 Example
 Serum Na+ = 125 mEq/L
 BUN = 140 mg/dL
 Blood glucose = 90 mg/dL
 Calculated and measured osmolality = 305 mOsm/kg

Posm = 2 x 125 + 90/18 + 140/2.8
 In this case, hyponatremia is associated with an
elevated plasma osmolality
 Effective osmolality = 255 mOsm/kg (calculation
excludes BUN) thus this patient may have symptoms
of hypotonicity despite an elevated plasma osmolality
Plasma Osmolality
Is plasma hypoosmolality
always associated with
hyponatremia?
YES
Posm ~ 2 x plasma [Na+]
Plasma Osmolality
Is hyponatremia always
associated with hypotonicity?
NO
Plasma Osmolality
 Example:
 Serum Na+ = 133 mEq/L
 BUN = 11 mg/dL
 Blood glucose = 500 mg/dL
 Effective osmolality (tonicity) = 294 mOsm/kg (2 x 133
+ 500/18)
 Hyponatremia is not always associated with
hypotonicity and thus direct therapeutic intervention
may not be required (in this example, treat underlying
hyperglycemia)
Plasma Osmolality
Do ineffective osmoles (urea,
ethanol, ethylene glycol,
methanol cause hyponatremia)?
NO. Remember these osmoles readily
move between fluid compartments
without causing water shifts
Plasma Osmolality
Do effective osmoles (glucose,
mannitol) cause hyponatremia?
Yes. These osmoles shift
water out of the cells
Clinical Examples of Hyponatremia
 Plasma Na+ = 120 mEq/L
 Blood glucose = 90 mg/dL
 BUN = 14 mg/dL
 Calc Posm = 250 mosmol/kg
Hypotonic
hyponatremia
 Meas Posm = 250 mosmol/kg
 Osmolar gap = 0 mosmol/kg
 Tonicity = 245 mosmol/kg
 risk of cerebral edema
Clinical Examples of Hyponatremia
 Plasma Na+ = 120 mEq/L
 Blood glucose = 90 mg/dL
 BUN = 14 mg/dL
 Calc Posm = 250 mosmol/kg
Pseudohyponatremia
( lipids, protein)
Note: absence of  osmolar
gap rule out this diagnosis
 Meas Posm = 290 mosmol/kg
 Osmolar gap = 40 mosmol/kg
 Tonicity = 285 mosmol/kg
No risk of cerebral edema
Clinical Examples of Hyponatremia
 Plasma Na+ = 120 mEq/L
 Blood glucose = 1350 mg/dL
 BUN = 14 mg/dL
 Calc Posm = 320 mosmol/kg
Hyponatremia caused
by hyperglycemia
 Meas Posm = 320 mosmol/kg
 Osmolar gap = 0 mosmol/kg
 Tonicity = 315 mosmol/kg
No risk of cerebral edema
Clinical Examples of Hyponatremia
 Plasma Na+ = 120 mEq/L
 Blood glucose = 90 mg/dL
Hyponatremia caused by mannitol
 BUN = 14 mg/dL
[Mannitol] = 75 mmol/L
 Calc Posm = 250 mosmol/kg
 Meas Posm = 325 mosmol/kg
 Osmolar gap = 75 mosmol/kg
 Tonicity = 320 mosmol/kg
 Osmolar gap (≠ hyperglycemia)
No risk of cerebral edema
Clinical Examples of Hyponatremia
 Plasma Na+ = 120 mEq/L
 Blood glucose = 90 mg/dL
 BUN = 14 mg/dL
 Calc Posm = 250 mosmol/kg
Hyponatremia due to ethanol
[EtOH] = 50 mmol/L
 Meas Posm = 300 mosmol/kg
 Osmolar gap = 50 mosmol/kg
 Tonicity = 245 mosmol/kg
 risk of cerebral edema
Clinical Examples of Hyponatremia
 Plasma Na+ = 120 mEq/L
 Blood glucose = 90 mg/dL
 BUN = 126 mg/dL
 Calc Posm = 290 mosmol/kg
 Meas Posm = 290 mosmol/kg
 Osmolar gap = 0 mosmol/kg
 Tonicity = 245 mosmol/kg
Hyponatremia caused by
renal failure
 risk of cerebral edema
Note: a normal measured
plasma osmolality does
not preclude an increased
risk of cerebral edema
Causes of Hyponatremia
Current Medical Diagnosis & Treatment, 2009
Hypotonic Hyponatremia
 Hypovolemic
 ↓ [Na+] = ↓↓TBNa/↓TBW
 Euvolemic
 ↓ [Na+] = ↔ TBNa/↑TBW
 Hypervolemic
 ↓ [Na+] = ↑TBNa/↑↑TBW
Laboratory Approach to
Hyponatremia
 Start with plasma osmolality to exclude
pseudohyponatremia (normal Posm) and hypertonic
hyponatremia (elevated Posm)
 When hypotonicity is confirmed, then assess clinically
patients’ volume status
Urine Osmolality
 Determine whether H2O excretion is normal or impaired
 Uosm < 100 mosmol/kg indicates that ADH is
appropriately suppressed
 Primary polydipsia
 Reset osmostat (when Posm is below normal)
 Low solute intake
 Uosm > 100 mosmol/kg occurs in majority of
hyponatremic patients and indicates impaired H2O
excretion
Urine Sodium Concentration
 Una < 20 mEq/L
 Hypovolemia due to extra-renal losses
 Edematous states in CHF, cirrhosis, nephrotic syndrome
 Dilutional effect in primary polydipsia due to very high
urine output
 Una > 20 mEq/L
 Hypovolemia due to renal losses
 Renal failure
 SIADH
 Reset osmostat
Other Labs
 Plasma uric acid concentration
 Hypouricemia (< 4mg/dL) in SIADH

Mild hypervolemia decreases proximal Na+ reabsorption,
leading to increased urinary uric acid excretion
 Blood urea nitrogen
 BUN may be < 5mg/dL in SIADH

Mild hypervolemia leads to urinary urea wasting
Case Illustration 1
 62 year old woman was admitted to the hospital for
abnormal liver-function tests. She had a history of
acute myelogenous leukemia and had undergone
transplantation of T-cell depleted allogeneic bone
marrow 2 years earlier. Medications include
tacrolimus, prednisone, MMF, ursodiol, atovaquone,
acyclovir and clarithromycin. Exam: afebrile, BP
130/75, HR 80. Appeared euvolemic. Labs revealed
serum sodium level 124 mmol/L.
What labs do you want to order?
NEJM 2003; 349:1465-9
Case Illustration 1
 Serum osmolality 294 mOsm/kg
 Urine osmolality 434 mOsm/kg
 Urine sodium 62 mmol/L
 BUN 43 mg/dL
 Serum creatinine 1.4 mg/dL
 Serum glucose 85 mg/dL
Calculated plasma osmolality 268 mOsm/kg
Case Illustration 1
 Total serum protein 5.1 gm/dL
 Lipemia was not observed
 Lipid profile (2 years prior)


Total cholesterol 181 mg/dL
Triglyceride 136 mg/dL
What would you do next?
Case Illustration 1
 Current lipid profile
 Total cholesterol 1836 mg/dL
 High-density lipoprotein 68 mg/dL
 Very low-density lipoprotein 42 mg/dL
 Triglyceride 208 mg/dL
 Calculated low-density lipoprotein 1726 mg/dL
 Serum [Na+] was 145 mmol/L when measured on a
blood-gas machine
What’s the cause for the patient’s hyponatremia?
Severe hypercholesterolemia
causing pseudohyponatremia
 Lipoprotein X
 Reflux of unesterified cholesterol and phospholipids
into the circulation from cholestatic biliary ducts

These cholesterol particles are insoluble in plasma water and
thus increase the solid fraction of plasma
 Occurs in patients with severe cholestasis (chronic graft-
versus-host disease, primary biliary cirrhosis)
 Serum is NOT lipemic (≠ severe hypertriglyceridemia)
Pseudohyponatremia
 Each liter of plasma contains
 ~ 930 ml water
 ~ 70 ml proteins and lipids
 High lipids or proteins reduce
plasma water; thus plasma [Na+],
measured per liter of plasma, is
artifactually low
 Plasma osmolality is unaffected
 Osmometer measures only the Na+
Measurement by an
osmometer
activity in the plasma water
What is the normal physiologic sodium concentration?
~ 151 mEq/L plasma water
Pseudohyponatremia
Serum [Na+] = 140 mEq/L
Serum [Na+] = 130 mEq/L
Solids 7%
1 liter
plasma
1 liter
plasma
Solids 14%
HYPERLIPIDEMIA
Water
93%
HYPERPROTEINEMIA
Na+
140 mEq
in 930 ml
Water
86%
OSMOLALITY
Measures solute per unit plasma water
140 mEq/930 ml = 151 mEq/liter = 130 mEq/860 ml
Na+ 130 mEq
in 860 ml
Measurements of Serum
+
[Na ]
 Flame emission spectrophotometer (FES)
 Measures serum [Na+]
 Ion-selective electrode (ISE)
 Measures [Na+] in plasma water
 Two methods:


Direct potentiometry (using undiluted serum sample)
 Blood gas machine
Indirect potentiometry (using diluted serum sample)
 Pseudohyponatremia can occur with FES or indirect
potentiometry, but not direct potentiometry
Flame Emission Spectrophotometer
 Ultrafine spray of diluted serum
sample is blown across a flame
 Measures the intensity of the light
emitted at the wavelength
characteristic of sodium
 Intensity is directly proportional to
the # sodium atoms in the sample
 Sample is compared to a standard
aqueous solution of known [Na+]
Ion-Selective Electrode
 Measures electrical potential
across a sodium-selective
membrane immersed in the
serum sample
 Electrical potential is a function
of the Na+ activity in the sample,
which correlate with sodium
concentration in serum water
(in undiluted serum)
Case Illustration 2
 43-year old woman with persistent renal failure two
months after a liver transplant, developed acute
hyponatremia during treatment of thrombocytopenia
with intravenous immune globulin (in 10% maltose).
Before therapy, her serum [Na+] was stable at 131 mmol/L.
One gm/kg of IVIG was administered over 12 hours on 2
successive days. After the second infusion, her serum
[Na+] was 118 mmol/L. After 4 hours of hemodialysis, the
serum [Na+] was 133 mmol/L. Hyponatremia recurred
during each of the four successive infusions of IVIG.
Direct potentiometry was used for the sodium assay.
What’s the cause for this patient’s hyponatremia?
Case Illustration 2
Annals of Internal Medicine 1993;118:526-8
Hypertonic Hyponatremia
 Effective osmoles result in water movement out of
cells, decreasing plasma [Na+] by dilution
 Causes
 Hyperglycemia-most common
 Mannitol
 Sorbitol
 Glycerol
 Radiocontrast agents
IVIG Causing Hyponatremia
 Hypertonic hyponatremia due to maltose intoxication
 Maltose given intravenously is normally metabolized by
maltase in the renal proximal tubule and excreted in the
urine
 Metabolic products of maltose metabolism can
accumulate in the setting of renal failure, raising the
plasma osmolality and causing dilutional hyponatremia
 Pseudohyponatremia
 IVIG increases the protein-containing nonaqueous
phase of plasma*
*NEJM 1998; 339:632
Case Illustration 3
 Late on the afternoon of 1 June 1981, a 46 year old
woman was admitted in a coma to a hospital in
Durban, South Africa. Before dawn that day, she had
begun a 90 km marathon race. But 20 km from the
finish line, she failed to recognize her husband who
had come to assist her. He convinced her to stop
running and drove her to the hospital. There she
received two liters of IV fluid but then suffered a grand
mal seizure and lapsed into coma. Serum [Na+] was 115
mmol/L. CXR showed evidence of pulmonary edema.
First case report of exercise-associated hyponatremia
complicated by encephalopathy and non-cardiogenic
(neurogenic) pulmonary edema
Br J Sports Med 2006;40:567-72
Case Illustration 3
What would be your immediate
treatment for this patient’s
hyponatrema?
I would give her 100 ml of 3% saline over 10 minutes
Acute Symptomatic Hyponatremia
(<48 hours): Treatment
 Immediate goal: ↑ [Na+] by 1-2 mEq/L/hr using 3% NS ± Lasix
 3% NS infusion at 1-2 ml/kg/hour or
 100 ml of 3% NS over 10 minutes, raising serum [Na+] 2-3 mEq/L
in a short period of time

If neurologic symptoms persist or worsen, can repeat 100 ml bolus 1 or 2
more times at 10-minute intervals
 Aim for cessation of neurologic symptoms, then reduce
correction rate
 Goal increase in serum [Na+]
 First 24 hours: < 8-10 mEq/L
 First 48 hours: < 18 mEq/L
Why the urgency to treat?
minutes
hours
days
NEJM 2000; 342:1581-9
Symptoms of Hyponatremia
 Signs and symptoms
 < 125-130 mEq/L: nausea, vomiting (earliest findings)
 < 115-120 mEq/L: headache, lethargy, obtundation
 < 110-115 mEq/L: seizures, coma, respiratory arrest
 Severity of neurologic dysfunction (cerebral edema) is
related to the rapidity of decline and level of plasma
Na+ concentration
 Cerebral edema occurs primarily with rapid (over 1-3
days) reduction in plasma [Na+]
Exercise-Associated Hyponatremia
Occurrence of hyponatremia
(< 135 mEq/L) during or up
to 24 hours after prolonged
physical activity
Risk Factors for EAH
 Excessive drinking (>1.5 L/hr) during event- major risk
 Exercise duration > 4 hrs or slow exercise pace
 Low body weight (overhydration in proportion to size)
 Female gender (may be explained by lower body weight)
 Pre-exercise overhydration
 Abundant availability of drinking fluids at event
 NSAIDS (not all studies)
 Extreme hot or cold environment
EAH: Overhydration
 Increased fluid intake associated with substantial
weight gain during the activity increases risk of
hyponatremia
 Athletes who gained > 4% body weight during exercise
had a 45% probability of developing hyponatremia
 However, excessive fluid consumption is not the sole
explanation for development of EAH
 Hyponatremia did not develop in 70% of the athletes
who overconsumed fluids and had an increase in body
weight
Proc Natl Acad Sci USA 2005; 102: 18550-5
Figure 1. Pathophysiologic factors in the development of exercise-associated hyponatremia (EAH)
Rosner, M. H. et al. Clin J Am Soc Nephrol 2007;2:151-161
Therapy of EAH
 Mild, asymptomatic hyponatremia (130-135 mEq/L)
 Fluid restriction and observation until spontaneous diuresis
occurs
 Avoid IV 0.9% normal saline due to risk of worsening
hyponatremia
 Severe, symptomatic hyponatremia
 Hypertonic saline (3% NS)


No cases of osmotic demyelination have been reported with
treatment of EAH
Indicated in patients manifesting encephalopathy and noncardiogenic pulmonary edema
 Vaptans-no data to indicate efficacy
EAH: Neurogenic Pulmonary Edema
Exercise-Associated Hyponatremia: Why Are Athletes
Still Dying?
Moritz, Michael; Ayus, Juan
Mechanism of non-cardiogenic pulmonary edema in
exercise-associated hyponatremia.
Clinical Journal of Sport Medicine. 18(5):379-381,
September 2008.
DOI: 10.1097/JSM.0b013e31818809ce
EAH: Neurogenic Pulmonary Edema
A depiction of the Ayus-Arieff syndrome.
Hyponatremia produces cytotoxic cerebral
edema which in turn leads to a neurogenic
pulmonary edema. Pulmonary edema
leads to hypoxia, which impairs brain cell
volume regulation, resulting in a vicious
cycle of worsening cerebral edema and
pulmonary edema. This syndrome can be
reversed by the prompt administration of
3% NaCl.
Exercise-Associated Hyponatremia: Why Are Athletes
Still Dying?
Moritz, Michael; Ayus, Juan
Clinical Journal of Sport Medicine. 18(5):379-381,
September 2008.
DOI: 10.1097/JSM.0b013e31818809ce
Prevention of EAH
 Avoid over consumption of fluids before, during and after
exercise
 Drink only according to thirst and no more than 400-800
ml per hour
 Monitor body weight to avoid weight gain
 No evidence that sports drinks can prevent EAH
 Most drinks have sodium content 10-20 mEq/L (hypotonic)
 No evidence that sodium supplementation can prevent
EAH
Case Illustration 4
 70 year old woman was admitted for coronary angiography
after developing chest pain. Mild HTN had been detected 8
months previously, followed by treatment with HCTZ. On
admission, serum sodium was normal at 140 mEq/L. Weight
70 kg. After the catheterization, pt was encouraged to
increase her fluid intake, and over the next 24 hours she
drank 5 L of water. On HOD #3, serum sodium was 127
mEq/L. On the following day, she underwent an angioplasty
and was once again advised to increase her fluid intake. The
next morning the patient complained of fatigue, nausea,
headache and dizziness; BP 95/60. Serum sodium was 118
mEq/L.
SMJ 1986; 79: 1456-7
Case Illustration 4
What labs would you order?
Serum osmolality 253 mOsm/kg
Urine sodium 57 mEq/L
Urine osmolality 525 mOsm/kg
How would you treat this patient?
Chronic Symptomatic Hyponatremia
(> 48 hrs or of unknown duration)
 Increase serum [Na+] by 0.5 to 1.0 mEq/L per hour
 Goal increase in serum [Na+]
 First 24 hours: < 8-10 mEq/L
 First 48 hours: < 18 mEq/L
What fluid would you use, to be
infused at what rate?
Hypotonic Hypovolemic
Hyponatremia
 Calculate sodium deficit
 Na+ deficit = TBW x Na+ deficit per liter


Male: TBW = 0.6 (wt in kg)
Female: TBW = 0.5 (wt in kg)
 Amount of sodium required to raise plasma [Na+] from
118 mEq/L to 124 mEq/L:

Na+ deficit = 0.5 (70kg) x (124 mEq/L – 118 mEq/L) = 210 mEq
 Volume of 0.9% NS required for correction

(210 mEq) x (1 liter/154 mEq Na+) = 1.36 liter
Hypotonic Hypovolemic
Hyponatremia
 Rate of correction
 Na+ deficit per liter/appropriate rate of correction

(124 mEq/L – 118 mEq/L)/0.5 mEq per L per hr = 12 hours
 1.36 L normal saline/12 hours = 113 ml per hour
 Caveats
 This calculation does not account for continued volume
losses during the treatment period
 As hypovolemia improves with 0.9% NS, ADH release
will be appropriately suppressed, resulting in rapid
excretion of the excess free water with risk of
overcorrection and osmotic demyelination
Thiazide-Induced Hyponatremia:
Pathogenesis
 Thiazides, by acting in
the cortex in the distal
tubule, do not interfere
with medullary function
and thus with ADHinduced water retention
 Cause urinary loss of
solutes in excess of water
Thiazide-Induced
Hyponatremia: Pathogenesis
 Underlying tendency to increase water intake (polydipsia)
 Impaired water excretion-2 different mechanisms:
 Volume depletion stimulates release of ADH
 Increased water retention independent of ADH


Via reduced ability to excrete a water load (unclear mechanism),
leading to slight volume expansion
These patients can develop thiazide-induced hyponatremia despite
NOT being volume depleted
 Can have normal BUN, creatinine and hypouricemia
 Initial weight gain
Thiazide-Induced Hyponatremia
 Most likely to occur in older women
 Hyponatremia develops within the first 1-2 weeks of
therapy
 Thiazides rarely cause severe hyponatremia associated
with encephalopathy/seizures
Case Illustration 5
 62 year old woman noted an unpleasant, sweet taste in
her mouth. She otherwise felt well and was taking no
medications. Because dysgeusia is a rare manifestation
of hyponatremia, her serum sodium level was tested
and was 122 mEq/L. The serum osmolality was 250
mOsm/kg, the urinary osmolality 635 mOsm/kg and
urinary sodium 85 mEq/L. Her thyroid function and
adrenal function were normal. A chest CT showed a
mass in the lower lobe of the left lung, which proved to
be a small-cell carcinoma.
What’s the cause of this patient’s hyponatremia
and your approach to therapy?
Chronic Asymptomatic
Hyponatremia: Treatment
 Correct hyponatremia very gradually
 Patients are at low risk of serious neurologic sequelae but
at risk of osmotic demyelination with rapid correction
 Fluid restriction is the mainstay of therapy
 Adequate intake of dietary protein and salt
 Urine output = solute excretion per day (mosmol)/urine
osmolality (mosmol/kg)
 Demeclocycline 300-600mg po BID
 Reduces urine osmolality
 Can be nephrotoxic
 Urea 30 g po per day
 Poorly tolerated
Syndrome of Inappropriate
Antidiuresis (SIAD)
Since not all patients with the syndrome of
inappropriate secretion of antidiuretic
hormone (SIADH) have elevated circulating
levels of arginine vasopressin, the term
syndrome of inappropriate antidiuresis
(SIAD) is a more accurate description of this
condition
.
Syndrome of Inappropriate
Antidiuresis (SIAD)
Type C
Figure 1 Osmoregulation of
plasma arginine vasopressin(AVP)
in patients with the syndrome of
inappropriate antidiuresis is
depicted for types A, B, C, and D. 1
mEq/L = 1 mmol/L.
Type A
Type B
Type D
Am J Med 2006; 119: S36-S42
Causes of SIAD
N Engl J Med 2007;356:2064-2072
Diagnosis of SIAD
N Engl J Med 2007;356:2064-2072
Treatment of SIAD
N Engl J Med 2007;356:2064-2072
Vasopressin-Receptor Antagonists
Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine, 2007
Vasopressin-Receptor Antagonists
Ellison D and Berl T. N Engl J Med 2007;356:2064-2072
Demographic and Baseline Characteristics of Patients in
the SALT-1 and SALT-2 Trials
N Engl J Med 2006;355:2099-2112
Change in the Average Daily Area under the Curve (AUC) for the
Serum Sodium Concentration from Baseline to Day 4 (Panel A) and
from Baseline to Day 30 (Panel B)
The increase in AUC for the
serum [Na+] was significantly
greater in the tolvaptan group
than in the placebo group
from baseline to Day 4 as well
as during the entire 30-day
study period
P<0.001 for all comparisons
Mild hyponatremia = 130-134 mmol/L
Marked hyponatremia < 130 mmol/L
N Engl J Med 2006;355:2099-2112
Mean Serum Sodium Concentrations According to the
Day of Patient Visit
Note: during the week
after discontinuation of
tolvaptan on day 30,
hyponatremia recurred
Asterisks indicate P<0.001 for the
comparison between tolvaptan and placebo.
Daggers indicate P<0.01 for the comparison
between tolvaptan and placebo. Tolvaptan
was discontinued on day 30. Circles denote
patients receiving tolvaptan, and squares
denote patients receiving placebo.
Horizontal lines indicate the lower limit of
the normal range for the serum sodium
concentration. Vertical lines indicate the
end of the treatment period. HN denotes
hyponatremia.
N Engl J Med 2006;355:2099-2112
EVEREST Trial: Baseline Participant
Characteristics
Effects of Oral Tolvaptan in Patients Hospitalized for
Worsening Heart Failure: The EVEREST Outcome Trial.
Konstam, Marvin; Gheorghiade, Mihai; Burnett, John;
Grinfeld, Liliana; Maggioni, Aldo; Swedberg, Karl;
Udelson, James; Zannad, Faiez; Cook, Thomas; Ouyang,
John; Zimmer, Christopher; Orlandi, Cesare
JAMA. 297(12):1319-1331, March 28, 2007.
3
Tolvaptan had no effect on all-cause mortality or the combined
end point of cardiovascular mortality or hospitalization for
worsening heart failure
Effects of Oral Tolvaptan in Patients Hospitalized for
Worsening Heart Failure: The EVEREST Outcome Trial.
Konstam, Marvin; Gheorghiade, Mihai; Burnett, John;
Grinfeld, Liliana; Maggioni, Aldo; Swedberg, Karl;
Udelson, James; Zannad, Faiez; Cook, Thomas; Ouyang,
John; Zimmer, Christopher; Orlandi, Cesare
JAMA. 297(12):1319-1331, March 28, 2007.
4
Tolvaptan had no effect on all-cause mortality or the
combined end point of cardiovascular mortality or
hospitalization for worsening heart failure
Kaplan-Meier Analyses of All-Cause Mortality and
Cardiovascular Mortality or Hospitalization for Heart Failure
Effects of Oral Tolvaptan in Patients Hospitalized for
Worsening Heart Failure: The EVEREST Outcome Trial.
Konstam, Marvin; Gheorghiade, Mihai; Burnett, John; Grinfeld,
Liliana; Maggioni, Aldo; Swedberg, Karl; Udelson, James;
Zannad, Faiez; Cook, Thomas; Ouyang, John; Zimmer,
Christopher; Orlandi, Cesare
JAMA. 297(12):1319-1331, March 28, 2007.
5