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Osmolality vs Effective OsmolalityOsmolality: 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 cellsExamples: Na+, glucose, mannitolNormal effective Posm = 270-285 mosmol/kg
Plasma OsmolalityNa+, glucose and BUN are major
determinants of plasma osmolalityPosm = 2 x plasma [Na+] + [Glucose]/18 +
[BUN]/2.8More important clinically to consider
effective osmolality than “total’’ osmolalityEffective 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 OsmolalityExample
Serum Na+ = 125 mEq/LBUN = 140 mg/dLBlood glucose = 90 mg/dLCalculated and measured osmolality = 305 mOsm/kg
Posm = 2 x 125 + 90/18 + 140/2.8In this case, hyponatremia is associated with an
elevated plasma osmolalityEffective osmolality = 255 mOsm/kg (calculation
excludes BUN) thus this patient may have symptoms of hypotonicity despite an elevated plasma osmolality
Is plasma hypoosmolality always associated with hyponatremia?
YESPosm ~ 2 x plasma [Na+]
Is hyponatremia always associated with hypotonicity?
NO
Plasma OsmolalityExample:
Serum Na+ = 133 mEq/LBUN = 11 mg/dLBlood 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)
Do ineffective osmoles (urea, ethanol, ethylene glycol, methanol cause hyponatremia)?
NO. Remember these osmoles readily move between fluid compartments without causing water shifts
Do effective osmoles (glucose, mannitol) cause hyponatremia?
Yes. These osmoles shift water out of the cells
Clinical Examples of HyponatremiaPlasma Na+ = 120 mEq/LBlood glucose = 90 mg/dLBUN = 14 mg/dLCalc Posm = 250 mosmol/kgMeas Posm = 250
mosmol/kgOsmolar gap = 0 mosmol/kgTonicity = 245 mosmol/kg
Hypotonic hyponatremia
risk of cerebral edema
Clinical Examples of HyponatremiaPlasma Na+ = 120 mEq/LBlood glucose = 90 mg/dLBUN = 14 mg/dLCalc Posm = 250
mosmol/kgMeas Posm = 290
mosmol/kgOsmolar gap = 40
mosmol/kgTonicity = 285 mosmol/kg
Pseudohyponatremia( lipids, protein)
Note: absence of osmolar gap rule out this diagnosis
No risk of cerebral edema
Clinical Examples of HyponatremiaPlasma Na+ = 120 mEq/LBlood glucose = 1350 mg/dLBUN = 14 mg/dLCalc Posm = 320 mosmol/kgMeas Posm = 320 mosmol/kgOsmolar gap = 0 mosmol/kgTonicity = 315 mosmol/kg
Hyponatremia caused by hyperglycemia
No risk of cerebral edema
Clinical Examples of HyponatremiaPlasma Na+ = 120 mEq/LBlood glucose = 90 mg/dLBUN = 14 mg/dLCalc Posm = 250
mosmol/kgMeas Posm = 325
mosmol/kgOsmolar gap = 75
mosmol/kgTonicity = 320 mosmol/kg
Hyponatremia caused by mannitol
[Mannitol] = 75 mmol/L
Osmolar gap (≠ hyperglycemia)
No risk of cerebral edema
Clinical Examples of HyponatremiaPlasma Na+ = 120 mEq/LBlood glucose = 90 mg/dLBUN = 14 mg/dLCalc Posm = 250
mosmol/kgMeas Posm = 300
mosmol/kgOsmolar gap = 50
mosmol/kgTonicity = 245 mosmol/kg
Hyponatremia due to ethanol
[EtOH] = 50 mmol/L
risk of cerebral edema
Clinical Examples of HyponatremiaPlasma Na+ = 120 mEq/LBlood glucose = 90 mg/dLBUN = 126 mg/dLCalc Posm = 290 mosmol/kgMeas Posm = 290
mosmol/kgOsmolar gap = 0 mosmol/kgTonicity = 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
Current Medical Diagnosis & Treatment, 2009
Hypotonic HyponatremiaHypovolemic
↓ [Na+] = ↓↓TBNa/↓TBWEuvolemic
↓ [Na+] = ↔ TBNa/↑TBWHypervolemic
↓ [Na+] = ↑TBNa/↑↑TBW
Laboratory Approach to HyponatremiaStart with plasma osmolality to exclude
pseudohyponatremia (normal Posm) and hypertonic hyponatremia (elevated Posm)
When hypotonicity is confirmed, then assess clinically patients’ volume status
Urine OsmolalityDetermine whether H2O excretion is normal or
impairedUosm < 100 mosmol/kg indicates that ADH is
appropriately suppressedPrimary polydipsiaReset 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 ConcentrationUna < 20 mEq/L
Hypovolemia due to extra-renal lossesEdematous states in CHF, cirrhosis, nephrotic
syndromeDilutional effect in primary polydipsia due to
very high urine outputUna > 20 mEq/L
Hypovolemia due to renal lossesRenal failureSIADHReset osmostat
Other LabsPlasma uric acid concentration
Hypouricemia (< 4mg/dL) in SIADH Mild hypervolemia decreases proximal Na+
reabsorption, leading to increased urinary uric acid excretion
Blood urea nitrogenBUN may be < 5mg/dL in SIADH
Mild hypervolemia leads to urinary urea wasting
Case Illustration 162 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.
NEJM 2003; 349:1465-9What labs do you want to order?
Case Illustration 1Serum osmolality 294 mOsm/kgUrine osmolality 434 mOsm/kgUrine sodium 62 mmol/LBUN 43 mg/dLSerum creatinine 1.4 mg/dLSerum glucose 85 mg/dL
Calculated plasma osmolality 268 mOsm/kg
Case Illustration 1Total serum protein 5.1 gm/dLLipemia was not observed
Lipid profile (2 years prior) Total cholesterol 181 mg/dL Triglyceride 136 mg/dL
What would you do next?
Case Illustration 1Current lipid profile
Total cholesterol 1836 mg/dLHigh-density lipoprotein 68 mg/dLVery low-density lipoprotein 42 mg/dLTriglyceride 208 mg/dLCalculated 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 pseudohyponatremiaLipoprotein 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 plasmaOccurs in patients with severe cholestasis
(chronic graft-versus-host disease, primary biliary cirrhosis)
Serum is NOT lipemic (≠ severe hypertriglyceridemia)
PseudohyponatremiaEach 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+ activity in the plasma water
Measurement by an osmometer
What is the normal physiologic sodium concentration?
~ 151 mEq/L plasma water
Solids 7%
Solids 14%
HYPERLIPIDEMIA
HYPERPROTEINEMIA
Serum [Na+] = 140 mEq/L
Serum [Na+] = 130 mEq/L
Na+ 140 mEq in 930 ml
Na+ 130 mEq in 860 ml
Water 93% Water
86%
1 liter plasma
1 liter plasma
OSMOLALITY
Measures solute per unit plasma water
140 mEq/930 ml = 151 mEq/liter = 130 mEq/860 ml
Measurements of Serum [Na+] Flame emission spectrophotometer (FES)
Measures serum [Na+] Ion-selective electrode (ISE)
Measures [Na+] in plasma waterTwo 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 SpectrophotometerUltrafine spray of diluted serum
sample is blown across a flameMeasures 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 ElectrodeMeasures 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 243-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?
Annals of Internal Medicine 1993;118:526-8
Hypertonic HyponatremiaEffective osmoles result in water movement
out of cells, decreasing plasma [Na+] by dilution
CausesHyperglycemia-most commonMannitolSorbitolGlycerolRadiocontrast agents
IVIG Causing HyponatremiaHypertonic hyponatremia due to maltose
intoxicationMaltose 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
PseudohyponatremiaIVIG increases the protein-containing nonaqueous
phase of plasma*
*NEJM 1998; 339:632
Case Illustration 3Late 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.
Br J Sports Med 2006;40:567-72
First case report of exercise-associated hyponatremia complicated by encephalopathy and non-cardiogenic (neurogenic) pulmonary edema
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 ± Lasix3% NS infusion at 1-2 ml/kg/hour or100 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 intervalsAim for cessation of neurologic symptoms, then
reduce correction rateGoal increase in serum [Na+]
First 24 hours: < 8-10 mEq/LFirst 48 hours: < 18 mEq/L
NEJM 2000; 342:1581-9
minutes
hours
days
Symptoms of HyponatremiaSigns and symptoms
< 125-130 mEq/L: nausea, vomiting (earliest findings)
< 115-120 mEq/L: headache, lethargy, obtundation< 110-115 mEq/L: seizures, coma, respiratory
arrestSeverity 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+]
Occurrence of hyponatremia (< 135 mEq/L) during or up to 24 hours after prolonged physical activity
Risk Factors for EAHExcessive drinking (>1.5 L/hr) during event- major
riskExercise duration > 4 hrs or slow exercise paceLow body weight (overhydration in proportion to
size)Female gender (may be explained by lower body
weight)Pre-exercise overhydrationAbundant availability of drinking fluids at eventNSAIDS (not all studies)Extreme hot or cold environment
EAH: OverhydrationIncreased fluid intake associated with
substantial weight gain during the activity increases risk of hyponatremiaAthletes 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 EAHHyponatremia 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
Rosner, M. H. et al. Clin J Am Soc Nephrol 2007;2:151-161
Figure 1. Pathophysiologic factors in the development of exercise-associated hyponatremia (EAH)
Therapy of EAHMild, asymptomatic hyponatremia (130-135
mEq/L)Fluid restriction and observation until spontaneous
diuresis occursAvoid IV 0.9% normal saline due to risk of
worsening hyponatremiaSevere, symptomatic hyponatremia
Hypertonic saline (3% NS) No cases of osmotic demyelination have been reported
with treatment of EAH Indicated in patients manifesting encephalopathy and
non-cardiogenic pulmonary edemaVaptans-no data to indicate efficacy
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
Mechanism of non-cardiogenic pulmonary edema in exercise-associated hyponatremia.
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
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.
Prevention of EAHAvoid over consumption of fluids before, during
and after exerciseDrink only according to thirst and no more than
400-800 ml per hourMonitor body weight to avoid weight gain
No evidence that sports drinks can prevent EAHMost drinks have sodium content 10-20 mEq/L
(hypotonic)No evidence that sodium supplementation can
prevent EAH
Case Illustration 470 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
What labs would you order?
Serum osmolality 253 mOsm/kgUrine sodium 57 mEq/LUrine 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 hourGoal increase in serum [Na+]
First 24 hours: < 8-10 mEq/LFirst 48 hours: < 18 mEq/L
What fluid would you use, to be infused at what rate?
Hypotonic Hypovolemic HyponatremiaCalculate 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 mEqVolume of 0.9% NS required for correction
(210 mEq) x (1 liter/154 mEq Na+) = 1.36 liter
Hypotonic Hypovolemic HyponatremiaRate 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 hourCaveats
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 ADH-induced 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 ADHIncreased 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 HyponatremiaMost likely to occur in older womenHyponatremia develops within the first 1-2
weeks of therapyThiazides rarely cause severe hyponatremia
associated with encephalopathy/seizures
Case Illustration 562 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: TreatmentCorrect 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 therapyAdequate intake of dietary protein and salt
Urine output = solute excretion per day (mosmol)/urine osmolality (mosmol/kg)
Demeclocycline 300-600mg po BIDReduces urine osmolalityCan be nephrotoxic
Urea 30 g po per dayPoorly tolerated
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
.
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.
Am J Med 2006; 119: S36-S42
Type A
Type B
Type C
Type D
N Engl J Med 2007;356:2064-2072
N Engl J Med 2007;356:2064-2072
N Engl J Med 2007;356:2064-2072
Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine, 2007
Ellison D and Berl T. N Engl J Med 2007;356:2064-2072
Vasopressin-Receptor Antagonists
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)
N Engl J Med 2006;355:2099-2112
P<0.001 for all comparisons
Mild hyponatremia = 130-134 mmol/LMarked hyponatremia < 130 mmol/L
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
Mean Serum Sodium Concentrations According to the Day of Patient Visit
N Engl J Med 2006;355:2099-2112
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.
Note: during the week after discontinuation of tolvaptan on day 30, hyponatremia recurred
3
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
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
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.
Kaplan-Meier Analyses of All-Cause Mortality and Cardiovascular Mortality or Hospitalization for Heart Failure
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