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Jointly sponsored by AACE and CME-University

Lewis S. Blevins, Jr., M.D.

Hyponatremia: Epidemiology

• 15% of hospitalized patients

• Serum sodium of <130 mEq/L– Incidence of 1% and prevalence of 2.5%

– 67% of cases were hospital acquired

• Settings– ICU 30%

– SAH30%

– TBI 12%

– CHF28%

– HIV 30%

Anderson RJ, et al. Ann Intern Med. 1985;102:164-168.

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Risk of Hyponatremia Increases with Age

Hawkins RC. Clin Chim Acta. 2003;337:169-172.

Hyponatremia in the Elderly

• Overall incidence of [Na+] <137 mmol/L ~7% 1

• Prevalence increases to 18-22% in chronic care

facilities, with 53% incidence of one or more

episodes of hyponatremia 2,3

• Mortality rate = 16% for patients over 65 with

hyponatremia versus 8% for those without

hyponatremia on admission 4

1. Caird FI, et al. Br Heart J. 1973; 35: 5 527-530. 2. Kleinfeld M, et al. Geriatr Soc .1979;27:156-161.

3. Miller MJ. J Am Geriatr Soc. 1995:43:1410-1413. 4. Terzian C, et al. J Gen Intern Med. 1994; 9:89–91

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Relationship Between Hospital Admission

Serum [Na+] and In-hospital Mortality

Wald R, et al. Arch Intern Med. 2010; 170:294-302.

0.20

0.15

0.10

0.05

110 115 120 125 130 135 140 145

Admission Serum [Na+] Concentration (mEq/L)

Predicted Probability of

In-Hospital Mortality

Hyponatremia and Mortality

1. Anderson RJ et al. Ann Intern Med. 1985;102:164-168. 2. Terzian C et al. J Gen Intern Med. 1994; 9:89–91.

3. Tierney VM, et al. J Gen Intern Med. 1986; 1:380-85.

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Mortality Rates are Uniformly Higher in

Hyponatremic Patients with a Variety of

Different Illnesses

n = 397 n = 169 n = 1,330 n = 153(Flear) (Westwater) (Samadi) (Flear)

Hyponatremia and Survival in

Congestive Heart Failure (CHF)

Adapted from: Goldberg A, et al. Arch Intern Med. 2006; 166:781 – 786.

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Hyponatremia in Cirrhosis

Impact on Survival

Kim R, et al. N Engl J Med. 2008; 359:1018-1026.

Neurohypophysis

• Arginine vasopressin

(AVP) secreting neurons

in SON and PVN

• Osmo- and thirst

receptors/centers in

anterior hypothalamus

• Ascending pathways from

ANS and brainstem

• Terminal boutons in

neurohypophysis

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Relationship between Plasma

Osmolarity and AVP

Arginine Vasopressin (AVP) Receptors

RECEPTOR LOCATION EFFECT

V1AVascular smooth

muscle, platelets

Vasoconstriction,

platelet aggregation

V1B Anterior pituitary ACTH release

V2Renal collecting

duct cellsFree water absorption

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Aquaporins

Adapted from Kaira PR, et al. Cardiovasc Res. 2001; 51:495-509.

Relationship between

Urine Osmolarity and AVP

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AVP Dynamics

Hyponatremia:

One of Many Algorithms

Adapted from Kumar S, & Berl T. Atlas of Diseases of the Kidney. 1999; 1.1-122.

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Clinical Features of CSW and SIADH

CSW SIADH

ECF* Decreased Increased

Hematocrit Increased Normal

Plasma albumin concentration Increased Normal

Plasma BUN/creatinine Increased Decreased

Plasma [K+] Normal or increased Normal

Plasma uric acid Normal or decreased Decreased

Treatment Normal saline Fluid restriction

*Determination of ECF is the primary way to differentiate CSW from SIADH.

BUN=blood urea nitrogen; CSW=cerebral salt wasting.

Palmer BF. Trends Endocrinol Metab. 2003; 14:182 – 187.

Unifying Hypothesis of Sodium and Water

Dysregulation After SAH

Mayer SA. The Neurologist. 1995; 1:71-85.

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Hyponatremia

• Disorders or processes that cause hyponatremia

are dynamic:

– Initiation

– Maintenance

– Recovery

• It is critical to ascertain where the patient might

be in their course as one initiates and measures

a response to management

Hyponatremia: Symptoms and Signs

FEATURE %

Nausea/Vomiting 71

Delirium/Confusion 50

Weakness 50

Lethargy 50

Myalgia/Cramps 21

Dizziness 21

Hiccups 14

Dysarthria 14

Illowsky BP, et al. Medicine. 1993; 72:359-373.

Headache!!!

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Correction of Hyponatremia Normalizes Gait

Stability in “Asymptomatic” Hyponatremia

serum [Na+] = 124 mEq/L

-500 -400 -300 -200 -100 -100 -2000

-40

-60

-80

0

-100

-120

140

-20

120

100

80

60

40

20

serum [Na+] = 130 mEq/L

-500 -400 -300 -200 -100 -100 -200

80

60

40

20

-20

-40

-60

-80

0

-100

-120

serum [Na+] = 139 mEq/L

100 200 200-500 -400 -300 -200 -100

80

60

40

20

-20

-40

-60

-80

0

-100

-120

serum [Na+] = 135 mEq/L

100 200 200-400 -300 -200 -100

80

60

40

20

-20

-40

-60

-80

0

-100

-120

100

Renneboog B, et al. Am J Med. 2006; 119:71.

Severe Hyponatremia168 patients Na+ <115 mEq/L

Nzerue CM, et al. J Natl Med Assoc. 2003;95:335-43.

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Treatments for Hyponatremia

Isotonic saline infusion

Hypertonic saline infusion

Vaptans: conivaptan, tolvaptan

Fluid restriction

Demeclocycline

Furosemide + NaCl

Mineralocorticoids

Urea

Vaptans: tolvaptan

long-term

short-term

Judicious use of 3% Saline

• Hyponatremic patients with significant

neurological symptoms, such as seizures,

severe altered mental status, or coma.

• The high likelihood of cerebral edema outweighs

the risk of possible demyelination.

• Target rate of correction is 1.5 to 2 mEq/L per

hour with 3% hypertonic saline for the first 3 to

4 hours, or more briefly, if symptoms improve or

the sodium level exceeds 120 mEq/L.

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Formula for Estimating Sodium Needs

3% Saline: An Alternative Approach

• Rate in mL/h is the desired rate of rise in Na+ in

mEq/L/h per kg body weight.

• Furosemide 20 mg iv.

• For a 70 kg patient with desired correction rate

of 1.5 mEq/L 3% saline infusion rate would be

105 mL/h.

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Fluid Restriction

?

Vasopressin Receptor Antagonists

DRUG ROUTE RECEPTOR EFFECTIVE DOSES

Conivaptan IV/Oral V1/V2 20-40 mg/d

Tolvaptan Oral V2 15-60 mg/d

Adapted from Ellison DH,& Berl T. N Engl J Med. 2007; 356:2064-2072.

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Conivaptan IV

8-10% experience rapid correction

Verbalis JG, et al. Clin Endocrinol (Oxf). 2008 Jul;69(1):159-68.

Conivaptan IV

Verbalis JG, et al. Clin Endocrinol (Oxf). 2008 Jul;69(1):159-68.

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SALT 1 and 2:

Mean Sodium Concentration Over Time

Schrier RW, et al. N Engl J Med. 2006;355:2099-2112.

Hyponatremia

Verbalis JG. TEM. 1992;3(1):1-7.

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Hyponatremia: Outcomes of Correction

Sterns RH, et al. J Am Soc Nephrol. 1994; 4:1533- 1530.

Osmotic Demyelination

Central Pontine Myelinolysis

Central Demyelination Syndrome

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Howard S A, et al. Radiographics .2009;29:933-938.

Central Demyelination

• Demyelination injury to oligodendrocytes

• Disruption of blood brain barrier may play a role

• Accumulation of microglials cells

• Release of pro-inflammatory cytokines

• Destruction of myelin

• Animal studies suggest minocycline and

lovastatin may be protective

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Clinical Features of Osmotic Demyelination

FEATURE %

Mutism/Dysarthria 71

Lethargy/Obtundation 57

Behavioral changes 29

Confusion 21

Movement difficulty 21

Muscle contractions 7

Dusphagia 7

Spasticity, rigidity, Babinski reflex, hyperreflexia, impaired gag reflex,

fasciculations, nonreactive or dilated pupils, snout, grasp or rooting reflexes,

impaired gait, ataxia,cognitive deficits.

Illowsky BP, et al. Medicine. 1993; 72:359-373.

Reducing Risks of Myelinolysis

• Limit correction of chronic hyponatremia to 10 to 12

mmol/L in 24 hours and to 18 mmol/L in 48 hours.

• When other recognized risk factors for myelinolysis

are present (menstruant women, hypokalemia, liver

disease, poor nutritional state, alcoholism, burns),

correction should not exceed 10 mEq/L/24h.

• In acute hyponatremia a more rapid initial

correction rate, roughly 1-2 mEq/L, is acceptable.

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Mismanagement of Hyponatremia

• 104 patients with Na+ <125 mEq/L in a 6 month period

• 42% of diagnoses incorrect

• 33% of patients with significant management errors

• Overall mortality 27%

– 41% in those with errors in management

– 20% in those managed appropriately

Huda MSB, et al. Postgrad Med J .2006; 82: 216–219.

Hyponatremia

The Endocrinologists Role

• Understand the epidemiology and

pathophysiology of hyponatremia

• Devise a systematic approach to the evaluation

of patients with hyponatremia

• Individualize therapy based on pathophysiology

• Educate colleagues and trainees

– Consultations

– Grand Rounds and other presentations

– Discussions

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