Hyponatremia

Charles Cline MD, PhDMedical Director

Otsuka Pharma Scandinavia

Hyponatremia

• Physiology of salt & water regulation• Classification• Pathophysiology• Symptoms and diagnosis• SIADH• Tolvaptan (SamscaTM)

Hyponatremia is the most common electrolyte disorder of hospitalized patients, with

incidences from 2-28% depending on the serum [Na+] level used to define hyponatremia:

[Na+] <135: 13-28% incidence1,2

[Na+] <130: 2-4% incidence1,3,4

1. Flear et al. Lancet 2:26-31, 19812. Hawkins. Clin Chim Acta 337:169-172, 20033. Natkunam et al. J Med 22:83-96, 19914. Berghmans et al. Support Care Cancer 8:192-197, 2000

Vasopressin Secretion

•Osmoreceptors

•Baroreceptors

•Posteriorlobe

•Pituitary

•VP is synthesised in the hypothalamus, stored in and released from the posterior pituitary

Control of Sodium Balance• P-Na+ = 135-145 mmol/l • Na+,Cl-, HCO3- = 86% extracellular fluid osmolality• P-Osmol = 285-295 mosm/kg • P-Osmol = 2× [Na]mmol/l + [urea]mmol.l +

[glucose]mmol/l• Main determinant of P-Na+ is plasma water content• Water content = intake + “insensible” losses + urinary

dilution• Urinary dilution most important, determined by

vasopressin

The Kidney

Vasopressin V2 receptor activation

Free water resorbtion

Signaling mechanisms involved in aquaporin-2 (AQP-2) regulation

Classification of hyponatremia

• Hypovolemic

• Hypervolemic

• Euvolemic (normovolemic)

HypovolemicExtrarenal loss, urine sodium <30 mmol/l• Dermal losses, such as burns, sweating • Gastrointestinal losses, such as vomiting, diarrhoea • Pancreatitis

Renal loss, urine sodium >30 mmol/l• Diuretics • Salt wasting nephropathy • Cerebral salt wasting • Mineralocorticoid deficiency (Addison's disease)

Hypervolemic*

Urine sodium <30 mmol/l• Congestive cardiac failure • Cirrhosis with ascites • Nephrotic syndrome

Urine sodium >30 mmol/l• Chronic renal failure

*Paradoxical retention of sodium and water despite a total body excess of each; baroreceptors in the arterial circulation perceive hypoperfusion, triggering an increase in vasopressin release and net water retention

Euvolemic

Urine sodium >30 mmol/l• Syndrome of inappropriate antidiuretic hormone secretion

(SIADH)† • Hypothyroidism • Hypopituitarism (glucocorticoid deficiency) • Water intoxication: Primary polydipsia• Excessive administration of parenteral hypotonic fluids• Post-transurethral prostatectomy

†SIADH is a diagnosis of exclusion

hyponatremia can be caused by depletion from electrolyte losses in excess of water, or by dilution from retained water

Levels of hyponatremia• 130-135 mmol/l = Mild hyponatremia: Usually

asymptomatic• <125-130 mmol/l = Moderate hyponatremia: Nausea,

malaise • <115-120 mmol/l = Severe hyponatremia: Headache,

lethargy, restlessness, disorientation follow, as the sodium concentration falls below

• Severe and rapidly evolving hyponatremia: seizure, coma, permanent brain damage, respiratory arrest, brain stem herniation, death

Hyponatremia - neurological manifestations

• headache

• irritability

• nausea/vomiting

• mental slowing

• confusion/delerium

• disorientation

• stupor/coma

• convulsions

• respiratory arrest

life-threatening, usually acute

symptomatic but less impaired; usually chronic

Neurological symptoms and P-Na concentrations

Arieff et al., Medicine 55:121-129, 1976

Symptoms• Related to severity and rapidity

of fall in P-Na• Creates osmotic gradient

between extracellular and intracellular fluid in brain cells, causing movement of water into cells, increasing intracellular volume, and resulting in tissue edema, raised intracranial pressure, and neurological symptoms

A B

Adaptive response to hyponatremia• Rapid adaptation

hours to days transport out of NaCl and K

• Slow adaptation loss of organic solutes including glutamate, taurine, myo-inositol, and glutamine from intracellular to extracellular compartments. Induces water loss and ameliorates brain swelling

Central Pontine Myelinolysis• Blood-brain barrier becomes permeable, rapid correction

of hyponatremia and allows complement mediated oligodendrocyte toxicity (can occur widely in the brain)

• Alcoholics with malnutrition, premenopausal or elderly women on thiazide diuretics, and patients with hypokalaemia or burns are at increased risk

• Neurological injury is typically delayed 2 to 6 days after elevation of Na concentration

• Neurological symptoms generally irreversible (dysarthria, dysphagia, spastic paraparesis, lethargy, seizures, coma, death)

White areas in the middle of the pons indicate massive demyelination of descending axons (corticobulbar and corticospinaltracts), usually associated with overly rapid correction of hyponatremia using hypertonic saline Wright, Laureno, Victor .Brain 102:361-385, 1979

Central Pontine Myelinolysis

Examination in patient with hyponatremia

Evaluation of volume status• Skin turgor • Pulse rate • Postural blood pressure • Jugular venous pressure • Consider central venous

pressure monitoring • Examination of fluid

balance charts

General examination for underlying illness

• Congestive cardiac failure • Cirrhosis • Nephrotic syndrome • Addison's disease • Hypopituitarism • Hypothyroidism

Investigations in patient with hyponatremia

• Urinary sodium • Plasma glucose and lipids* • Renal function • Thyroid function • Peak cortisol during short synacthen test† • Plasma and urine osmolality‡ • If indicated: chest x ray, and computed tomography and

magnetic resonance imaging of head and thorax

*Pseudohyponatraemia due to artefactual reduction in plasma sodium in the presence of marked elevation of plasma lipids or proteins should no longer be seen with the measurement of sodium by ion specific electrodes; hyperglycaemia causes true hyponatraemia, irrespective of laboratory method.

†May be unhelpful in pituitary apoplexy, in which patients may still “pass” the test.‡For SIADH: plasma osmolality < 270 mosm/kg with inappropriate urinary concentration (> 100 mosm/kg), in a euvolaemic

patient after exclusion of hypothyroidism and glucocorticoid deficiency).

Robertson et al. Robertson et al. Am J Med Am J Med 72:339-353, 198272:339-353, 1982

P-AVP levels are inappropriately elevated in most patients with SIADH

0

7

1011

98

654321

230 240 250 260 270 280 290 300 310

Plasma Osmolality (mOsm/kg)

Pla

sma

Vas

op

ress

in (

pg

/mL

)

Normal Normal RangeRange

Causes of SIADH

Cancers Pulmonary diseases

CNS disorders Drugs Other

Carcinomas (eg. lung, oropharynx, gastro-intestinal tract, genitourinary tract)

LymphomasSarcomas

Infections (eg. pneumonia, abscess, tuberculosis)

AsthmaCystic fibrosis COPDAcute respiratory failurePositive-pressure ventilation

Infection (eg. encephalitis, meningitis)

Bleeding and masses

(eg. SAH, brain tumours, head trauma)

Other (eg. multiple sclerosis, Guillain-Barre syndrome)

Stimulation of vasopressin release or enhancement of its action

(eg. chlorpropamide, SSRIs, carbamazepine, anti-psychotic drugs

Vasopressin analogues

(eg. desmopressin, oxytocin, vasopressin)

Hereditary IdiopathicTransient

(eg. endurance exercise, general anaesthesia)

AIDS

Ellison DH, et al. N Engl J Med. 2007;356:2064-72. Verbalis JG, et al. Am J Med. 2007;120(11A):S1-S21.

AIDS = Acquired immune deficiency syndrome; CNS = Central nervous system; COPD = Chronic obstructive pulmonary disease; SAH = Subarachnoid haemorrhage; SSRIs = selective serotonin reuptake inhibitors

Diagnosing SIADHEssential and supplemental diagnostic criteria for SIADH

Essential1,2

• Hyponatraemia < 135 mmol/l• Plasma hypo-osmolality < 275 mOsm/Kg• Urine osmolality > 100 mOsm/Kg• Clinical euvolaemia

• No clinical signs of hypovolaemia (orthostatic decreases in blood pressure, tachycardia, decreased skin turgor, dry mucous membranes)

• No clinical signs of hypervolaemia (oedema, ascites)• Increased urinary sodium excretion with normal salt and water intake ≥ 30 mmol/l• Absence of other potential causes of euvolaemic hypo-osmolality

• Exclude hypothyroidism, hypocortisolism, renal disease and recent diuretic use

Supplemental1,3

• Failure to correct hyponatraemia after 0.9% saline infusion• Correction of hyponatraemia through fluid restriction• Abnormal water load test over 4 hours• Plasma vasopressin inappropriately elevated relative to plasma osmolality

Ellison DH, et al. N Engl J Med. 2007;356:2064-2072. Janicic N, et al. Endocrinol Metab Clin N Am. 2003;32:459-481. Verbalis JG, et al. Am J Med. 2007;120(11A):S1-S21.

Types of SIADH

Type Characteristics Prevalence

Type A VP release independent of plasma

osmolality

35%

Type B Osmotic threshold for VP release

Osmoregulation around osmolar

set point

30%

Type C Failure to suppress VP at low osmolality

Normal response to osmotic stimulation

Type D N ● Normal osmoregulated VP release

Unable to excrete water load

<10%

5

10

15

20

280 290 300 310 320

Plasma osmolality (mOsm/kg)P

lasm

a A

VP

(pm

ol/l)

A

B

C

Assessing and managing hyponatremia

Disadvantages of conventional treatmentsTreatment Mechanism 1-3 Disadvantage 1-3

Fluid restriction Induces negative water balanceIncreases plasma osmolality and plasma sodium

Poor patient complianceSlow onset of action (2-3 days, may prevent discharge)

Hypertonic saline Increases water excretion and replaces sodium Difficult to administer (IV)Complex calculations needed to estimate appropriate rate of sodium correctionRisk of overly rapid sodium correction leading to osmotic demyelination syndrome

Demeclocycline Impairs vasopressin action at renal tubulesInduces nephrogenic diabetes insipidus

Unpredictable response (may cause hypernatraemia)Renal and liver toxicitiesSlow onset of action (3-4 days)

Urea Decreases sodium excretion Renal and liver toxicitiesPoor compliance due to bad taste

Lithium Impairs vasopressin action at renal tubules Inconsistent resultsRarely used due to toxicity

Loop diuretics Increase water excretion by inhibiting sodium and chloride re-absorption in the loop of Henle and distal tubule

Electrolyte imbalance (eg. hypokalaemia, exacerbation of hyponatraemia)

1. Verbalis J, et al. Am J Med. 2007; 120(11 Suppl 1): S1-21.

2. Douglas I. Cleve Clin J Med. 2006; 73 Suppl 3: S4-12.

3. Ellison DH, et al. N Engl J Med. 2007;356:2064-2072. 28

SIADHIntracerebral aneurysm

135

125

120

115pla

sma

Na+

mm

ols

/L

3% NaClN-salineFluid restrict