1. Hyponatremia

2. Osmolality vs Effective Osmolality
Osmolality: total number of particles in an aqueous solution (mosmol/kg H2O)
Normal Posm = 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 = mosmol/kg

3. 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)
1. two reflects the osmotic contribution of the anion accompanying Na+ and 18 and 2.8 represent the conversion of the plasma glucose concentration and the BUN from units of milligrams per deciliter (mg/dL) into millimoles per liter (mmol/L). Under normal conditions, glucose and urea contribute less than 10 mosmol/kg, and the plasma Na+ concentration is the main determinant of the Posm (Posm ~ 2 x plasma [Na+])
2. (UpToDate Chapter 1B: Units of solute measurement)
The osmotic pressure generated by a solution is proportional to the number of particles per unit volume of solvent, not to the type, valence, or weight of the particles.
The unit of measurement of osmotic pressure is the osmole. One osmole (osmol) is defined as one gram molecular weight (1 mol) of any nondissociable substance (such as glucose) and contains 6.02 x 1023 particles. In the relatively dilute fluids in the body, the osmotic pressure is measured in milliosmoles (one-thousandth of an osmole) per kilogram of water (mosmol/kg). Since most solutes are measured in the laboratory in units of millimoles per liter, milligrams per deciliter, or milliequivalents per liter, the following formulas must be used to convert into mosmol/kg:
    mosmol/kg   =     n  x   mmol/L
or, from Eqs. (1) and (2),
(Eq. 4)      mosmol/kg    =    (n   x   mg/dL  x  10)   ÷   mol wt
(Eq. 5)      mosmol/kg    =    (n   x   meq/L)   ÷   valence
where n is the number of dissociable particles per molecule. When n = 1, as for Na+, Cl-, Ca2+, urea, and glucose, 1 mmol/L will generate a potential osmotic pressure of 1 mosmol/kg. If, however, a compound dissociates into two or more particles, 1 mmol/L will generate an osmotic pressure greater than 1 mosmol/kg.
3. (UpToDate Chapter 7A: Exchange of water between the cells and ECF)
 The osmotic contributions of glucose and urea, both of which are measured in milligrams per deciliter, can be calculated from Eq. (1):
(Eq. 1)    mosmol/kg   =   (mg/dL  x  10)  ÷  mol wt
 The molecular weight of glucose is 180 and that of the two nitrogen atoms in urea (since urea is measured as the blood urea nitrogen or BUN) is 28. Therefore, the Posm can be estimated from:
(Eq. [Na+] )  +   ([glucose]/18)   +   (BUN/2.8)
The effective plasma (and extracellular fluid) osmolality is determined by those osmoles that act to hold water within the extracellular space. Since urea is an ineffective osmole:
(Eq. 3)    Effective [Na+] )  +   ([glucose]/18)
The normal values for these parameters are:
    Plasma [Na+]   =      meq/L     [Glucose]   =      mg/dL, fasting     BUN   =     10-20 mg/dL     Posm   =      mosmol/kg     Effective Posm   =      mosmol/kg
Under normal circumstances, glucose accounts for only 5 mosmol/kg, and Eq. (3) can be simplified to:
(Eq. 4)    Effective [Na+]
Thus, in most conditions, the plasma Na+ concentration is a reflection of the Posm, a finding consistent with the fact that Na+ salts are the principal extracellular osmoles.

4. Plasma Osmolality
Is hyponatremia always associated with a low plasma osmolality? NO

5. 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 / /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

6. Plasma Osmolality
Is plasma hypoosmolality always associated with hyponatremia?
YES
Posm ~ 2 x plasma [Na+]

7. Plasma Osmolality Is hyponatremia always associated with hypotonicity?NO

8. 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 /18)
Hyponatremia is not always associated with hypotonicity and thus direct therapeutic intervention may not be required (in this example, treat underlying hyperglycemia)

9. Plasma Osmolality
Do ineffective osmoles (urea, ethanol, ethylene glycol, methanol cause hyponatremia)?
These osmoles readily move between fluid compartments without causing water shifts.
NO. Remember these osmoles readily move between fluid compartments without causing water shifts

10. Plasma Osmolality
Do effective osmoles (glucose, mannitol) cause hyponatremia?
These osmoles shift water out of the cells
Yes. These osmoles shift water out of the cells

11. Clinical Examples of Hyponatremia
Plasma Na+ = 120 mEq/L
Blood glucose = 90 mg/dL
BUN = 14 mg/dL
Calc Posm = 250 mosmol/kg
Meas Posm = 250 mosmol/kg
Osmolar gap = 0 mosmol/kg
Tonicity = 245 mosmol/kg
Hypotonic hyponatremia
 risk of cerebral edema

12. Clinical Examples of Hyponatremia
Plasma Na+ = 120 mEq/L
Blood glucose = 90 mg/dL
BUN = 14 mg/dL
Calc Posm = 250 mosmol/kg
Meas Posm = 290 mosmol/kg
Osmolar gap = 40 mosmol/kg
Tonicity = 285 mosmol/kg
Pseudohyponatremia
( lipids, protein)
Note: absence of  osmolar gap rule out this diagnosis
UpToDate: Dilutional hyponatremia, similar to that induced by hyperglycemia or the administration of hypertonic mannitol, is a potential complication of IVIG therapy [72]. (See "Complications of mannitol therapy".) IVIG is often administered in a 10 percent maltose solution. Maltose is normally metabolized by maltase in the proximal tubule. In patients with renal failure, however, maltose can accumulate in the extracellular fluid, raising the plasma osmolality and lowering the plasma sodium concentration by dilution as water moves out of the cells down the favorable osmotic gradient. Maltose accumulation can also lead to an osmolal gap, as the measured plasma osmolality is greater than that estimated from the contributions of sodium, potassium, glucose, and urea. Affected patients are not at risk for symptoms of hyponatremia, since the plasma osmolality is modestly increased, not reduced.
Pseudonatremia can also be seen due to IVIG administration. This phenomenon is due to the protein load, which increases the non-aqueous phase of plasma. Because the concentration of sodium is physiologically regulated in the aqueous phase, but the laboratory sodium determination uses the total plasma volume of the sample, an artifactual dilution of sodium results [73].
No risk of cerebral edema

13. Clinical Examples of Hyponatremia
Plasma Na+ = 120 mEq/L
Blood glucose = 1350 mg/dL
BUN = 14 mg/dL
Calc Posm = 320 mosmol/kg
Meas Posm = 320 mosmol/kg
Osmolar gap = 0 mosmol/kg
Tonicity = 315 mosmol/kg
Hyponatremia caused by hyperglycemia
No risk of cerebral edema

14. Clinical Examples of Hyponatremia
Plasma Na+ = 120 mEq/L
Blood glucose = 90 mg/dL
BUN = 14 mg/dL
Calc Posm = 250 mosmol/kg
Meas Posm = 325 mosmol/kg
Osmolar gap = 75 mosmol/kg
Tonicity = 320 mosmol/kg
Hyponatremia caused by mannitol
[Mannitol] = 75 mmol/L
 Osmolar gap (≠ hyperglycemia)
No risk of cerebral edema

15. Clinical Examples of Hyponatremia
Plasma Na+ = 120 mEq/L
Blood glucose = 90 mg/dL
BUN = 14 mg/dL
Calc Posm = 250 mosmol/kg
Meas Posm = 300 mosmol/kg
Osmolar gap = 50 mosmol/kg
Tonicity = 245 mosmol/kg
Hyponatremia due to ethanol
[EtOH] = 50 mmol/L
Stat Ref! ACP Medicine
Beer potomania  Patients who subsist on beer (a practice known as beer potomania) are susceptible to hyponatremia because of their low rates of solute excretion (beer contains little protein or electrolyte). Reduced delivery of the glomerular filtrate to distal diluting sites limits the amount of water that can be excreted. Nonosmotic stimuli to vasopressin secretion caused by nausea or gastrointestinal fluid losses or by treatment with thiazide diuretics are often contributing factors.
 risk of cerebral edema

16. 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

17. Causes of Hyponatremia
Normal plasma osmolality
Severe hyperlipidemia (TG > 1500 mg/dL) and hyperproteinemia (total protein > 8 g/dL)
Posttransurethral resection of prostate
Use of isosmotic but non-Na+ containing flushing solution (glycine)
Unlike hyperlipidemia/hyperproteinemia, plasma [Na+] is truly reduced although Posm is normal
Current Medical Diagnosis & Treatment, 2009

18. Hypotonic Hyponatremia
Hypovolemic
↓ [Na+] = ↓↓TBNa/↓TBW
Euvolemic
↓ [Na+] = ↔ TBNa/↑TBW
Hypervolemic
↓ [Na+] = ↑TBNa/↑↑TBW

19. 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

20. 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
Reset Osmostat
Has normal osmotic responses to Posm but ADH release is not suppressed until Posm falls well below normal (≠ SIADH in which there is nonsuppressible ADH release)
Plasma Na concentration is subnormal but remains stable (usually mEq/L)
Associated with hypovolemia, psychosis, malnutrition, quadriplegia and pregnancy
Therapy for hyponatremia is unnecessary

21. 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

22. Other Labs Plasma uric acid concentration Blood urea nitrogen
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

23. 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

24. 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

25. 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?

26. 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?

27. 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)

28. 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+ activity in the plasma water
Measurement by an osmometer
What is the normal physiologic sodium concentration?
~ 151 mEq/L plasma water

29. Pseudohyponatremia Measures solute per unit plasma water
Serum [Na+] = 140 mEq/L
Serum [Na+] = 130 mEq/L
Solids 7%
Solids 14%
1 liter plasma
HYPERLIPIDEMIA
1 liter plasma
Water 93%
HYPERPROTEINEMIA
Water 86%
Na+ 130 mEq in 860 ml
Na+ 140 mEq in 930 ml
OSMOLALITY
Measures solute per unit plasma water
140 mEq/930 ml = 151 mEq/liter = 130 mEq/860 ml

30. 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
Am J Med 1989; 86: 317
Why, then, continue to measure serum sodium using
techniques that create the potential for such mismanagement?
First, most patients have serum lipid and
protein concentrations well below the levels necessary
to significantly alter the serum sodium determination
[9]. For these patients, the conventional measurement
techniques are perfectly adequate. Second, many direct-
reading ISEs are low-capacity instruments that
cannot handle the large number of specimens sent to
clinical laboratories [16,18]. Third, conversion of a
clinical laboratory to exclusive use of direct-reading
ISE would require adoption of a new reference range
for serum sodium and re-education of the entire clinical
and laboratory staffs.

31. 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+]

32. 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)

33. 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?

34. Case Illustration 2
Annals of Internal Medicine 1993;118:526-8

35. 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

36. 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

37. 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

38. 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

39. 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

40. Why the urgency to treat?
minutes
hours
Effects of Hyponatremia on the Brain and Adaptive Responses.
Within minutes after the development of hypotonicity, water gain causes swelling of the brain and a decrease in osmolality of the brain. Partial restoration of brain volume occurs within a few hours as a result of cellular loss of electrolytes (rapid adaptation). The normalization of brain volume is completed within several days through loss of organic osmolytes from brain cells (slow adaptation). Low osmolality in the brain persists despite the normalization of brain volume. Proper correction of hypotonicity reestablishes normal osmolality without risking damage to the brain. Overly aggressive correction of hyponatremia can lead to irreversible brain damage.
days
NEJM 2000; 342:1581-9

41. Symptoms of Hyponatremia
Signs and symptoms
< mEq/L: nausea, vomiting (earliest findings)
< mEq/L: headache, lethargy, obtundation
< 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+]

42. Exercise-Associated Hyponatremia
Occurrence of hyponatremia (< 135 mEq/L) during or up to 24 hours after prolonged physical activity

43. 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

44. 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:

45. 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)
Rosner, M. H. et al. Clin J Am Soc Nephrol 2007;2:
ADH level can be increased by
Exercise
nonspecific stresses such as pain and emotion
Volume depletion
Heat
Release of inflammatory cytokines by the exercising skeletal muscle
Even small increases in plasma ADH can cause significant water retention and hyponatremia, especially in cmobinatino with excessive water intake.
Gastrointestinal blood flow and water absorption from the stomach and intestine may be impaired during exercise. When the athlete stops activity, water absorption may increase rapidly and significantly.
Impaired diluting capability
During exercise, there is release of catecholamines and angiotensin II that leads to an increase in Na and water reabsorption in the proximal tubule, thus decreasing the amount of filtrate that is delivered to the distal diluting segments.
Renal blood flow and GFR are decreased in the setting of endurance exercise and further limit the delivery of filtrate to the diluting segments of the kidney.
Sweating
Na concentration in sweats is usually mEq/L
Volume of sweats during exercise varies (250ml/hr to > 2000 ml/hr), being less in more fit athletes
Despite loss of the hypotonic sweat fluid, athletes can become hyponatremic due to ingestion of more hypotonic fluids (water or sports drinks) and volume loss from sweats may stimulate ADH secretion.
Exchangeable sodium
Up to ¼ of the total body sodium may exist in bone and cartilage stores that are not osmotically active but potentially recruitable into an osmotically active form.
Athletes who develop EAH either cannot mobilize the exchangeable pool of sodium or may osmotically inactivate sodium
Regulation of exchange of sodium between these compartments may be regulated by hormonal factors such as angiotensin II or aldosterone.
Rosner, M. H. et al. Clin J Am Soc Nephrol 2007;2:

46. 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 non-cardiogenic pulmonary edema
Vaptans-no data to indicate efficacy

47. EAH: Neurogenic Pulmonary Edema
Exercise-Associated Hyponatremia: Why Are Athletes Still Dying?
Moritz, Michael; Ayus, Juan
Clinical Journal of Sport Medicine. 18(5): , September 2008.
DOI: /JSM.0b013e ce
Mechanism of non-cardiogenic pulmonary edema in exercise-associated hyponatremia.

48. 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): , September 2008.
DOI: /JSM.0b013e ce

49. Prevention of EAH
Avoid over consumption of fluids before, during and after exercise
Drink only according to thirst and no more than ml per hour
Monitor body weight to avoid weight gain
No evidence that sports drinks can prevent EAH
Most drinks have sodium content mEq/L (hypotonic)
No evidence that sodium supplementation can prevent EAH

50. 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:

51. 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?

52. 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?

53. 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

54. 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

55. 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
INTRODUCTION — Hyponatremia is an occasional but potentially fatal complication of diuretic therapy. Virtually all cases of severe diuretic-induced hyponatremia have been due to a thiazide-type diuretic [1-6]. A loop diuretic is much less likely to induce this problem unless the diuretic has induced volume depletion [7] or water intake is very high (since loop diuretics partially impair urinary diluting capacity).
PATHOGENESIS — The difference in hyponatremic risk between thiazide-type and loop diuretics may be related to differences in their tubular site of action. (See "Diuretics and calcium balance", for a review of the transporters affected by the different diuretic classes).
Loop diuretics inhibit NaCl reabsorption in the thick ascending limb of the loop of Henle. The reabsorption of NaCl without water in the medullary aspect of this segment is normally the primary step in the generation of the hyperosmotic gradient in the medullary interstitium; in the presence of ADH, the highly concentrated interstitium allows water to be reabsorbed in the medullary collecting tubule down a favorable osmotic gradient between the tubular lumen and the interstitium.
Administration of a loop diuretic interferes with this process by impairing the accumulation of NaCl in the medulla. Thus, although the loop diuretic can increase ADH levels by inducing volume depletion, responsiveness to ADH is reduced because of the impairment in the medullary gradient [8]. As a result, water retention and the development of hyponatremia will be limited, unless distal delivery is very low or water intake is very high.
The thiazides, in comparison, act in the cortex in the distal tubule; as a result, they do not interfere with medullary function or therefore with ADH-induced water retention. In some cases, the combination of increased sodium and potassium excretion (due to the diuretic) and enhanced water reabsorption (due to ADH) can result in the excretion of urine with a sodium plus potassium concentration higher than that of the plasma [3]. Loss of this fluid can directly promote the development of hyponatremia independent of the degree of water intake.
As with other diuretic-induced fluid and electrolyte complications, hyponatremia develops within the first one to two weeks of therapy if diuretic dose and dietary intake remain relatively constant [1,3]. After this period, the patient is in a new steady-state in which further sodium and water loss do not occur. Although later onset has been described [5,9], such patients must have had some perturbation in the steady state (eg, development of heart failure) or an increase in diuretic dose. (See "Time course of diuretic-induced electrolyte complications".)

56. 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

57. 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

58. 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?

59. 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 mg po BID
Reduces urine osmolality
Can be nephrotoxic
Urea 30 g po per day
Poorly tolerated

60. 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

61. Syndrome of Inappropriate Antidiuresis (SIAD).
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
4 types of inappropriate antidiuresis:
A: moderate to marked increases in plasma AVP that fluctuate widely with no discernible relation to the increase in plasma osmolality. The pattern is caused by erratic, unregulated release of AVP (30% patients with SIAD). Urine osmolality is fixed at the highest level possible.
B: plasma AVP is not as high and does not change until plasma osmolality and Na rise into the normal range. At that point, AVP begins to rise appropriately in direct relation to the strength of the osmotic stimulus. Pattern is caused by a slow, constant “leak” of AVP (30% of patients with SIAD). Urine osmolality is fixed but at a lower level than in type A.
C: reset osmostat (downward resetting of osmoregulation). 30% of patients with SIAD
D: AVP is suppressed to undetectable levels and remains so until plasma osmolality and Na increase to within the normal range. At that point, plasma AVP begins to rise normally in close correlation with further increases in plasma osmolality and sodium Thus, osmoregulation of the hormone appears to be completely normal. Despite lack of detectable AVP in plasma under hyponatremic conditions, patients fail to dilute their urine. Can sometimes be caused by mutation that constituently activates the AVP V2 receptor.
Type D
Am J Med 2006; 119: S36-S42

62. Causes of SIAD
N Engl J Med 2007;356:

63. Diagnosis of SIAD Table 2. Diagnosis of SIAD.
N Engl J Med 2007;356:

64. Treatment of SIAD
N Engl J Med 2007;356:

65. Vasopressin-Receptor Antagonists
Mechanism of action of vasopressin antagonists. The binding of arginine vasopressin (AVP) to V2 receptors stimulates the synthesis of aquaporin (AQP)-2 water channel proteins and promotes their transport to the apical surface. At the cell membrane, aquaporin-2 permits selective free water reabsorption down the medullary osmotic gradient, ultimately decreasing serum osmolarity and increasing fluid balance. V2 antagonists work by preventing AVP from binding to its cognate receptor. cAMP = cyclic adenosine monophosphate; Gs = Gs protein; PKA = protein kinase A.  (Modified from deGoma EM, Vagelos RH, et al: Emerging therapies for the management of decompensated heart failure: From bench to bedside. J Am Coll Cardiol 48:2397, 2006).
Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine, 2007

66. Vasopressin-Receptor Antagonists
Ellison D and Berl T. N Engl J Med 2007;356:

67. Demographic and Baseline Characteristics of Patients in the SALT-1 and SALT-2 Trials
N Engl J Med 2006;355:

68. 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 = mmol/L
Marked hyponatremia < 130 mmol/L
N Engl J Med 2006;355:

69. 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:

70. 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): , March 28, 2007. 3

71. 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): , March 28, 2007. 4

72. 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): , March 28, 2007.
Kaplan-Meier Analyses of All-Cause Mortality and Cardiovascular Mortality or Hospitalization for Heart Failure 5