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