HIPONATREMIA SI HIPERNATREMIA

CONF. DR. CRISTIAN SERAFINCEANU

INDNBM N. PAULESCU BUCURESTI

Mantra for Hyponatremia

Hyponatremia is a water problem, not a sodium problem

McLlwaine JF, Corwin HL: Hypernatremia and hyponatremia: In Grenvik A (Editor) Textbook of Critical Care, 5th Edition, 2005.

Mechanisms of Osmolality Regulation

Sodium Balance
Hypertonicity

Water Balance

Natriuresis (Na+ Excretion)

Na+ Appetite (No Salt Intake)

Thirst (Water Intake)

Vasopressin (Water Retention/ Increased Thirst)

Set- point

Natriuresis (Na+ Retention)

Na+ Appetite (Salt Intake)

Thirst (No Water Intake)

Vasopressin (Water Excretion)

Hypotonicity

Fluid Compartments/Solutes
Distribution of water- due to osmotic forces Na is mainly extracellular, K is intracellular Serum osmol = 2(Na)+ BUN/2.8 + Gluc/18
Sodium is the primary determinant

Serum osmol tightly regulated (275 290) Mechanisms for regulation

If osmol 1. thirst mechanism, 2. ADH Effective circulating volume also ADH

Regulation of a Renal Water Channel by Arginine Vasopressin (AVP)

Generation of medullary hypertonicity Normal function of the thick ascending limb of loop of Henle Urea delivery Normal medullary flow
AQP-3 Recycling Vesicle cAMP NaCl H2O GFR
H2O

Endocytic Retrieval AQP-2

ATP
ADH ADH NaCl GS H2O NaCl NaCl H2O ADH H2O H2O AQP-4 AVP GS PKA

AQP-2
H2O AQP-2 Exocytic Insertion Recycling Vesicle

Determinants of delivery of NaCl to distal tubule:

NaCl NaCl

GFR Proximal tubular fluid and

solute (NaCl) reabsorption H2O H2O

NaCl

Basolateral

Luminal

Water Delivery NaCl Movement Solute Concentration

Collecting system water permeability determined by: Presence of arginine vasopressin Normal collecting system

Incidence of Hyponatremia
Hyponatremia is a common electrolyte disorder
occurring in up to 15% of hospitalized patients1

Euvolemic hyponatremia, most often caused by

SIADH, accounts for about 60% of all types of chronic hyponatremia1

If not treated appropriately, hyponatremia may

lead to significant morbidity and death2,3

1. Baylis PH. Int J Biochem Cell Biol. 2003;35:1495-1499. 2. Adrogu HJ. Am J Nephrol. 2005;25:240-249. 3. Huda MSB et al. Postgrad Med J. 2006;82:216-219.

Hyponatremia in the Medical Literature

1935 Helwig et al. Acute postoperative hyponatremia could cause death or permanent brain damage from cerebral edema. Few case studies between 1935 and 1980s 1986 Arieff et al. 15 previously healthy, young women suffered permanent or fatal brain damage after receiving hypotonic fluids postoperatively. 1986-1995 Arieff et al. Deaths and permanent brain damage from postoperative hyponatremia increased to more than 100 cases.
Helwig FC et al. J Am Med Assoc. 1935;104:1539-75. Arieff AI. N Engl J Med.1986;314:1529-35.

Epidemiology of Hyponatremia
Most common electrolyte abnormality1
Seen most commonly among the elderly, intensive care patients, postoperative patients, patients with intracranial disorders, heart failure patients and exercise2

Occurs in 1/3 of all hospitalized patients1

13% of marathon runners3

1Hoorn

EJ et al. Nephrol Dial Transplant. 2006;21:7076. 2Chen S et al. Nat Clin Pract Neph. 2007;3:82-96. 3Kipps C et al. Br J Sports Med. 2009, Jul 20.

Morbidities in Hospitalized Patients With Symptomatic Hyponatremia

Symptoms of Hyponatremic Encephalopathy
60 50 Altered Sensorium

Patients (%)

40 30 20 10 0 Seizures Gait & Nausea Disturbance Vomiting Falls & Dysarthria

n=89

Coma

Single-center, retrospective review at large US hospital over a 4-year period (1997-2001) 168 patients with serum [Na+] <115 mEq/L Symptoms of hyponatremic encephalopathy in 89 of 168 patients (53%) No documented symptoms in 79 of 168 patients (47%)

Nzerue CM et al. J Natl Med Assoc. 2003;95:335-343.

Hyponatremia Mortality
Mortality is dependent on severity Mortality rate of individuals with serum sodium < 130 mEq/L is between 40% and 50% in acute hospital cases1 Surgical patients with hyponatremia
Fatality rate of 11% compared to 0.2% of patients without hyponatremia2

Misdiagnosis
Leads to many cases of hyponatremia-induced fatalities3

1Martin

RJ. J Neurol Neurosrug Psychiatry. 2004;75(suppl III):iii22-8. 2Anderson RJ et al. Ann Intern Med. 1985;102:164-168. 3Hoorn EJ et al. Nephrol Dial Transplant. 2009;2(suppl III):iii5-11.

KaplanMeier survival plots for hyponatraemic patients (Na 125mmol/l) by aetiology.

Clayton J et al. QJM 2006;99:505-511

The Author 2006. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Gines P and Schrier RW, NEJM, 2009

Gines P and Schrier RW, NEJM, 2009

Gines P and Schrier RW, NEJM, 2009

Water Intake & Exercise

Endurance races
Dehydration Vomiting/diarrhea NSAID use

What Causes Exercise-Induced Hyponatremia?

AVP levels in collapsed runners after the 2004 Boston Marathon 43% with sodium < 135 mmol/l had measurable levels of AVP. Many of those collapsed did not urinate during the race. 10 Exercise-induced hyponatremia is not due to sodium loss but rather from fluid retention.

20

Plasma AVP Level (pg/ml)

15

0
124 126 128 130 132 134 136

Serum Sodium (mmol/l)

Siegel AJ et al. Am J Med. 2007;120: 461.e11-7.

Thiazide-Induced Hyponatremia

Mechanism1
Decreased urinary dilution Mild volume depletion stimulates AVP, water retention, and syndrome of inappropriate antidiuretic hormone secretion (SIADH) Elderly have impaired renal function and impaired ability to excrete excess fluid

3-4 times increased risk in women2,3 One study found that 63% of cases occurred within 14 days of starting treatment with a thiazide diuretic2 A second study found that 37% of patients developed thiazideinduced hyponatremia more than 1 year after starting the thiazide3

1. Miller M. J Gen Intern Med. 2006;54:345-353; 2. Sonnenblick M et al. Chest. 1993;103:601606; 3. Sharabi Y et al. J Human Hypertension. 2002;16:631-635.

Pharmacotherapy
Antidepressants
SSRIs have been shown to have 2 to 4 times the risk of causing hyponatremia as tricyclics1-3 6 times the risk compared to a control1-3 Fluoxetine and paroxetine are the most likely to cause hyponatremia1-3

Most commonly prescribed

Mechanism causing hyponatremia is unknown
OJ et al. Psych Ann. 2003; 33(5):333-9. KL et al. BrJ Clin Pharm. 2002; 53:363-9. 3Palmer BF et al. Ann Pharmacother. 2003; 37:1694-1702.
2Movig
1Bogunovic

Pathophysiology of Hyponatremia
Acute
Develops under 48 hours

Chronic
Develops over more than 48 hours No seizures Less fatal

Soupart A & Decaux G. Clin Nephrol. 1996;46:149-69.

Signs and Symptoms

Loss of consciousness Restlessness Irritability Seizures Muscle weakness,
cramps, spasms

Signs and Symptoms-Hyponatremia

Headache Confusion Lethargy Fatigue Appetite loss Nausea and vomiting

Patient History
Current conditions
Diseases/disorders

Past conditions Current medications

Diuretic medications

Psychotropics
NSAIDS

Current lifestyle
Exercise

Controversies
Symptomatic hyponatremia rapid correction

Can cause demyelination in the brain

Treating the elderly

Medication interactions Other diseases

Laboratory Assessment
Blood osmolality test Urine osmolality ?! Blood and urine sodium

Diagnostic Approach-Hyponatremia
Serum sodium 136 mmol/l

Exclude or correct for Pseudohyponatremia Hyperglycemia-induced hyponatremia

Hypotonic hyponatremia Severe hyponatremia ( 125 mmol/l) Documented as acute (< 48 hours) Convulsions or coma Mild hyponatremia (125-136 mmol/l) Documened as chronic (> 48 hours) Asymptomatic or mild symptoms

Start hypertonic saline (Raise 1-2 mmol/l/h until symptoms abate and not exceeding 8-12 mmol/l/day)

Start diagnostic evaluation and select therapy appropriate for cause of hyponatremia

Hoorn EJ & R Zietse. Nephron Physiol. 2008;108:46-59.

Diagnostic Approach-Etiology of Hyponatremia

Vasopressin activity? Urine > serum osmolality Yes (Thiazide) diuretics No Non-renal loss Diarrhea Burns Low effective circulating volume Heart failure Liver cirrhosis Endocrine causes Hypopituitarism Adrenal insufficiency Hypothyroidism Salt wasting Cerebral Renal Vomiting Polydipsia and/or impaired water excretion independent of vasopressin Low dietary solute intake Primary polydipsia Beer potomania Renal failure No

Above diagnosis excluded or unlikely Syndrome of inappropriate antidiuretics No obvious cause Undetectable or normal vasopressin levels Unresponsiveness to vasopressin receptor antagonists Water loading test abnormal Nephrogenic syndrome of inappropriate antidiuretics Once a diagnosis is established, examine therapeutic options Water loading test normal

Reset osmostat

Hoorn EJ & R Zietse. Nephron Physiol. 2008;108:46-59.

Historical Treatment
Mercurial diuretics

Can increase urine sodium output

Low-sodium diet

Non-compliance issues
Fluid restriction

Non-compliance issues
Intravenous hypertonic saline

Difficult to control
Thiazide diuretics

Can increase urine sodium output

General Principles in the Treatment of Acute Hyponatremia

Neurologic consequences can follow both the failure to promptly treat as well as the excessively rapid rate of correction of hyponatremia Presence or absence of significant neurologic signs and symptoms must guide treatment Acuteness or chronicity of hyponatremia impacts the rate at which serum [Na+] is corrected If drug-induced SIADH, discontinue the drug The half-life or offset of effect of the offending drug should be taken into consideration Frequent monitoring of serum [Na+] is needed

Kumar S, Berl T. In: Atlas of Diseases of the Kidney. 1999:1.1-1.21; Adrogue HJ, Madias NE. N Engl J Med. 2000;342:1581-1589.

Ideal Therapy for Acute Hyponatremia

Prompt but safe correction of [Na+] in 24 to 48 hr:
12 mEq/L in the first 24 hr 18 mEq/L in the first 48 hr

Produces increased water excretion without electrolyte excretion (Na+ and K+) - AQUARESIS Eliminates or decreases need for fluid restriction

Predictable and reliable action

Quick onset/offset: easily titratable No unexpected side effects/toxicities

No drug/disease interactions
Cost-effective data available

Aquaresis

Aquaresis is defined as the solute-free excretion of water by the kidney

Because electrolytes represent a major component of urine solutes, aquaresis is also electrolyte-sparing
Measured by increases in EWC and is calculated from the urine volume and from the plasma and urine [Na+] and [K+] Typically accompanied by increased urine output and reduced urine osmolality

Distinguished from diuresis (increased urine output accompanied by electrolyte excretion)

EWC=effective water clearance. Vaprisol (conivaptan hydrochloride injection). Prescribing information. Deerfield, Ill: Astellas Pharma US, Inc.; February 2007; Verbalis JG. J Mol Endocrinol. 2002;29:1-9.

Traditional Treatments for Hyponatremia

Acute Saline infusion
isotonic hypertonic (caution ODS)

Fluid restriction (slow effect) Furosemide + NaCl (not in CHF) Chronic Demeclocycline Mineralocorticoids Lithium Urea
Cawley M. Ann Pharmacother 2007;41:epub DOI 10.1345/aph.1H502

Effects of Hyponatremia on the Brain

Normal brain (normal osmolality)
Immediate effect of hypotonic state

Water gain (low osmolality)

Rapid adaptation

Osmotic demyelination

Improper therapy (rapid correction)

Proper therapy (slow correction) Water

Loss of organic osmolytes (low osmolality)

Slow adaptation

Loss of sodium, postassium, and chloride (low osmolality)

Adapted from Adrogue HJ & Madias NE. N Engl J Med. 2000;342:15819.

Osmotic Demyelination Syndrome Can Be a Consequence of Inappropriate Management of Hyponatremia

An overly rapid increase in serum [Na+] (>12 mEq/L/24 hours) may result in serious sequelae1 Presence or absence of significant neurologic signs and symptoms must guide treatment2 Acute or chronic hyponatremia impacts the rate at which correction should be undertaken3

Image with permission of www.dizziness-andbalance.com/disorders/central/brainstem%20strokes.htm.

1. Vaprisol (conivaptan hydrochloride injection) Prescribing information. Deerfield, Ill: Astellas Pharma US, Inc.; February 2007; 2. Kumar S, Berl T. In: Atlas of Diseases of the Kidney. 1999;1.1-1.22; 3. Adrogu HJ et al. N Engl J Med. 2000;342:1581-1589.

VAPRISOL (conivaptan hydrochloride injection)

Vaprisol is indicated for the treatment of euvolemic hyponatremia (eg, SIADH, or in the setting of hypothyroidism, adrenal insufficiency, pulmonary disorders, etc) in hospitalized patients Vaprisol is also indicated for the treatment of hypervolemic hyponatremia in hospitalized patients Not indicated for the treatment of congestive heart failure (effectiveness and safety have not been established in these patients)

Vaprisol (conivaptan hydrochloride injection). Prescribing information. Deerfield, Ill: Astellas Pharma US, Inc.; February 2007; Verbalis JG. J Mol Endocrinol. 2002;29:1-9.

CONCLUSIONS I

Hypernatremia (Na+ > 145 mEq)

Hypernatremia is caused by a relative deficit of water in relation to sodium which can result from
Net water loss: accounts for majority of cases of hypernatremia
pure water loss hypotonic fluid loss

Hypertonic gain results from iatrogenic sodium loading

Goal of Treatment
Reduce serum sodium concentration to 145 mmol/L Make allowance for ongoing obligatory or incidental losses of hypotonic fluids that will aggravate the hypernatremia In patients with seizures prompt anticonvulsant therapy and adequate ventilation

Management
A two-pronged approach: 1. Addressing the underlying cause: stopping GI loss, controlling pyrexia, hyperglycemia, correcting hypercalcemia or feeding preparation, moderating lithium induced polyuria 2. Correcting the prevailing hypertonicity: rate of correction depends on duration of hypernatremia to avoid cerebral edema

Effects of Hypernatremia on the Brain and Adaptive Responses

Administration of Fluids
Preferred route: oral or feeding tube IV fluids if oral not feasible Except in cases of frank circulatory compromise, isotonic saline is unsuitable Only hypotonic fluids are appropriate-pure water, 5% dextrose, 0.2 % saline, 0.45% saline- the more hypotonic the infusate, the lower the infusion rate required

Summary of Managing Hypernatremia

1. Isotonic saline unsuitable except in ECF volume depletion causing hemodynamic instability 2. Switch to hypotonic solutions as soon as circulatory status stabilized

3. Avoid excessive rapid correction or over correction

4. Select the most hypotonic infusate suitable with appropriate allowances for ongoing fluid losses 5. Most important - reassess infusion prescriptions at regular intervals based on the clinical status and