Osmolality vs Effective Osmolality Osmolality: total number of particles in an aqueous solution...

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






Hyponatremia caused by mannitol

[Mannitol] = 75 mmol/L

Osmolar gap (≠ hyperglycemia)






Hyponatremia due to ethanol

[EtOH] = 50 mmol/L


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


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

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

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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.

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JAMA. 297(12):1319-1331, March 28, 2007.

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JAMA. 297(12):1319-1331, March 28, 2007.

Kaplan-Meier Analyses of All-Cause Mortality and Cardiovascular Mortality or Hospitalization for Heart Failure

Osmolality vs Effective Osmolality Osmolality: total number of particles in an aqueous solution...

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