Transcript Slide 1

Hyponatremia
Charles Cline MD, PhD
Medical 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, 1981
2. Hawkins. Clin Chim Acta 337:169-172, 2003
3. Natkunam et al. J Med 22:83-96, 1991
4. Berghmans et al. Support Care Cancer 8:192-197, 2000
Vasopressin Secretion
•VP is synthesised in the hypothalamus, stored in and released from the posterior pituitary
•Osmoreceptors
•Pituitary
•Posterior
lobe
•Baroreceptors
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
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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)
Hypovolemic
Extrarenal 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
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headache
irritability
nausea/vomiting
mental slowing
confusion/delerium
disorientation
stupor/coma
convulsions
respiratory arrest
symptomatic but
less impaired;
usually chronic
life-threatening,
usually acute
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)
Central Pontine Myelinolysis
White areas in the middle of
the pons indicate massive
demyelination of descending
axons (corticobulbar and
corticospinal
tracts), usually associated with
overly rapid correction
of hyponatremia using
hypertonic saline
Wright, Laureno, Victor .
Brain 102:361-385, 1979
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
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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).
Plasma Vasopressin (pg/mL)
P-AVP levels are inappropriately elevated in
most patients with SIADH
11
10
9
8
7
6
5
4
3
2
1
0
Normal
Range
230
240
250
260
270
280
290
Plasma Osmolality (mOsm/kg)
Robertson et al. Am J Med 72:339-353, 1982
300
310
Causes of SIADH
Cancers
Carcinomas
(eg. lung,
oropharynx,
gastro-intestinal
tract,
genitourinary tract)
Lymphomas
Sarcomas
Pulmonary
diseases
Infections
(eg. pneumonia,
abscess,
tuberculosis)
Asthma
Cystic fibrosis
COPD
Acute respiratory
failure
Positive-pressure
ventilation
CNS disorders
Drugs
Infection
(eg. encephalitis,
meningitis)
Bleeding and
masses
(eg. SAH, brain
tumours, head
trauma)
Other
(eg. multiple
sclerosis, GuillainBarre syndrome)
Stimulation of
vasopressin release or
enhancement of its
action
(eg.
chlorpropamide,
SSRIs,
carbamazepine,
anti-psychotic drugs
Vasopressin
analogues
(eg. desmopressin,
oxytocin,
vasopressin)
Other
Hereditary
Idiopathic
Transient
(eg. endurance
exercise, general
anaesthesia)
AIDS
AIDS = Acquired immune deficiency syndrome; CNS = Central nervous system; COPD = Chronic obstructive pulmonary disease; SAH = Subarachnoid
haemorrhage; SSRIs = selective serotonin reuptake inhibitors
Ellison DH, et al. N Engl J Med. 2007;356:2064-72. Verbalis JG, et al. Am J Med. 2007;120(11A):S1-S21.
Diagnosing SIADH
Essential and supplemental diagnostic criteria for SIADH
Essential1,2
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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
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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
20
Type A
 VP release independent of plasma
35%
A
osmolality
  Osmotic threshold for VP release
30%
 Osmoregulation around  osmolar
set point
Type C
 Failure to suppress VP at low osmolality
 Normal response to osmotic stimulation
Type ND  ● Normal osmoregulated VP release
 Unable to excrete water load
<10%
15
Plasma AVP (pmol/l)
Type B
10
5
B
C
280
290
300
310
320
Plasma osmolality (mOsm/kg)
Assessing and managing hyponatremia
Disadvantages of conventional treatments
Treatment
Mechanism 1-3
Disadvantage 1-3
Fluid restriction
Induces negative water balance
Increases plasma osmolality and plasma sodium
Poor patient compliance
Slow 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 correction
Risk of overly rapid sodium correction leading to osmotic
demyelination syndrome
Demeclocycline
Impairs vasopressin action at renal tubules
Induces nephrogenic diabetes insipidus
Unpredictable response (may cause hypernatraemia)
Renal and liver toxicities
Slow onset of action (3-4 days)
Urea
Decreases sodium excretion
Renal and liver toxicities
Poor compliance due to bad taste
Lithium
Impairs vasopressin action at renal tubules
Inconsistent results
Rarely 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.
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SIADH
plasma Na+ mmols/L
Intracerebral aneurysm
135
Fluid restrict
125
120
115
N-saline
3% NaCl