Water distribution

Intracellular 28L

(66%)

Extracellular 14L

(33%)

Plasma

3.5 L

(8%)

Interstitial

10.5 L

(25%)

Cell membrane

Osmotic pressure

Osmi (K+) = Osmo (Na+)

Capillary wall

Colloid osmotic pressure

(albumin)

vs.

Hydrostatic pressure

Water Balance

INTAKE OUTPUT

Unregulated: food & social drink Insensible and obligate loss

Regulated: thirst AVP modulated water output

Thirst

Hyperosmolar stimulus hypothalamic osmoreceptors threshold 1 to 4% above basal

Hypovolaemic stimulus baroreceptors threshold 10 - 15% ? absent in man (inconvenient with postural change!)

Normally inactive as unregulated input is in excess

AVP secretion

Synthesized in hypothalamic supraoptic and paraventricular nuclei

Stored and released from posterior pituitary (> 1 week store!)

Interacts via V2 receptors to insert aquaporin-2 water channels

0

2

4

6

8

10

270 280 290 300 310

Plasma osmolality (mOsm/Kg)

Pla

sma

AV

P (

pm

ol/L

)

0

100

Su

bje

ctiv

e th

irst

(an

alo

gu

e sc

ale)

BASAL

AVP secretion - stimulation

Osmolar threshold within ‘normal range’

High ‘gain’ (i.e steep curve and high renal

sensitivity)

AVP secretion - stimulation

Osmotic stimulus high sensitivity

Hypovolaemic stimulus high threshold (>10% depletion)

AVP secretion - stimulation

Osmotic stimulus high sensitivity

Hypovolaemic stimulus high threshold (>10%)

Nausea most powerful known

stimulus

Stress e.g. post-operative

Drugs ‘SIADH’

Integration of thirst and AVP

Unregulated water intake supplies water in excess of need

Excess water is excreted

AVP secretion regulates free water clearance

AVP maintains osmolality within narrow limits

This avoids ‘inconvenient’ thirst and water-seeking behaviour

Thirst kicks-in when deficiency reaches harmful levels

Renin-aldosterone system

Renin - aldosterone system

Renin substrate

Angiotensin I (inactive)

Angiotensin II

Aldosterone

Increased perfusion pressure

Renal sodium & water retention

Vasoconstriction Thirst

Low renalBlood flow

KIDNEYJuxtaglomerularapparatus

Renin

High K+

Low arterial pressure

Carotid sinus

Low sodium intake

Causes of hyponatraemia

Lipaemia / hyperproteinaemia ?

HYPONATRAEMIA

Hyperglycaemia ?

Total body waterVolume

expandedVolumedepleted

Renalloss

Extra-renalloss

No oedema Oedema

DiureticsAddison’s

VomitingDiarrhoea

SIADHHypothyroid

NephroticCirrhosisCCF

UNa >20 <10<10 >20

Rx Normal saline Fluid restriction

Pseudo-hyponatraemia

Compensatoryhyponatraemia

YES

YES

NO

NO

Pseudohyponatraemia

Na+Na+Na+Na+Na+Na+Na+Na+Na+Na+Na+Na+

Na+Na+

K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+

K+

Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl-

Cl-

HCO3- HCO3

- HCO3- HCO3

- HCO3- HCO3

- HCO3- HCO3

-

ADH Aldosterone

Measured sodium concentration 140 mmol/L

Pseudohyponatraemia

Na+Na+Na+Na+Na+Na+Na+Na+Na+Na+Na+Na+

Na+Na+

K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+

K+

Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl-

Cl-

HCO3- HCO3

- HCO3- HCO3

- HCO3- HCO3

- HCO3- HCO3

-

ADH Aldosterone

Measured sodium concentration 120 mmol/L

Osmolality (solute concentration in water) normal

Case

A 17-year old woman was seen in outpatients with a two month history of increasing lethargy and giddiness. She was found to be hyperpigmented and had postural hypotension

Serum Ref rangeSodium 132 mmol/L

133 – 143Potassium 5.4 mmol/L 3.6 – 4.6Urea 8.5 mmol/L 3.0 – 7.0Creatinine 101 umol/L 55 - 110

Case

A 66-year old man was admitted for investigation of possible bronchogenic carcinoma

Serum Ref rangeSodium 121 mmol/L133 – 143Potassium 4.1 mmol/L 3.6 –

4.6Urea 4.4 mmol/L 3.0 –

7.0

SIADH - pathogenesis

Inappropriately high AVP levels

Ongoing (unregulated) water intake

Blood volume rises

>10% expansion inhibits aldosterone and triggers

natriuresis

Syndrome of Inappropriate ADH

Bartter and Schwartz criteria (1967)

hyponatraemia with hypotonicity of plasma

urine osmolality inappropriately high

ongoing renal sodium excretion

absence of oedema or volume depletion

normal renal and adrenal function

i.e. Clinically normovolaemic hyponatraemia

Syndrome of Inappropriate ADH

Sodium <120 mmol/L Lethargy Anorexia Nausea and vomiting Irritability Headache Muscle weaknes Cramps

Sodium <110 mmol/L Drowsiness Confusion Depressed reflexes Extensor plantar

responses Seizures Coma Death

Symptoms relate to rate of fall as well as severity

No oedema because water distributed in both compartments

Causes of SIADH

Neoplasia Carcinoma of

lung, pancreas, bladder

Leukaemia Thymoma Lymphoma Sarcoma Mesothelioma

Neurological disorders Meningitis Encephalitis Brain tumour Subarachnoid haemorrhage Cerebral and cerebellar

atrophy Guillain-Barré syndrome Acute intermittent

porphyria Shy-Drager syndrome Head injury

Lung disease Pneumonia TB Pneumothor

ax Asthma IPPV

Causes of SIADH

Drugs Vasopressin Oxytocin Vinca alkaloids Cisplatin Chlorpropamide Carbamazepine Phenothiazines Thiazides MAOI’s SSRI’s Tricyclics Nicotine Ecstacy

Miscellaneous Acute psychosis Post-operative state AIDS Glucocorticoid deficiency Severe hypothyroidism Idiopathic

Patterns of AVP release in SIADH

Diagnosis of SIADH

Essential criteria True plasma hypo-osmolality (<275 mOsm/Kg) Inappropriate urine osmolality (>~100 mOsm/Kg) Euvolaemia; no oedema, ascites or intravascular hypovolaemia Urine sodium not low (>30 mmol/L during normal intake) Normal renal, adrenal, and thyroid function

Supplemental criteria Low serum urea and urate Unable to excrete >80% of water load (20mL/Kg) in 4h and/or failure to

achieve urine osmolality <100 mOsm/Kg No significant rise in serum [Na] after volume expansion but

improvement with fluid restriction

Treatment of SIADH

Identification and treatment of underlying cause

Clearance of excess water not necessary in asymptomatic chronic hyponatraemia fluid restriction to 500 - 1000 mL/24h Demeclocycline

600 to 1,200 mg daily may take three weeks to reach maximal effect caution in renal or hepatic insufficiency

Specific V2 receptor antagonists (OPC-31260)

Treatment of SIADH

Hypertonic saline Only if significantly symptomatic

Calculate sodium required

Na+ req. (mmol) = (125 – [Na+]) x 0.6 x body weight (kg)

Also measure and re-infuse urinary sodium output

Rate of increase not usually >0.5 mmol/L/h

? combine with i.v. furosemide

Stop saline when sodium reaches 120 - 125 mmol/L

Other causes of euvolameic hyponatraemia

Psychogenic hyponatraemia Massive water intake (20 - 30 L/day) Urine osmolality <100 mOsm/kg

Beer-drinker’s potomania High volume low solute drinks impair ability to excrete water

Hypothyroidism Reset osmostat

Pure glucocorticoid deficiency Cortisol is required for renal free water excretion

Cerebral salt wasting

SIADH 1º increase in AVP Inappropriate urine

hyperosm. Volume-expansion Suppressed aldosterone Appropriate natriuresis Decreased urea and urate

Treatment: fluid restriction

CSW Cerebral damage Reduced SNS efferents +/-

BNP Inappropriate natriuresis Volume-depletion Volume mediated AVP

release Appropriate urine hyperosm.

Treatment: Normal saline infusion

Case 4

A 53-year old bachelor was brought to the A&E department having been found semi-comatose. He was known to be a heavy drinker of alcohol. On examination he was jaundiced. His abdomen was distended; there was hepatomegaly and evidence of ascites. He had ankle oedema.

Serum Ref rangeCreatinine 84 µmol/L 75 – 120Urea 10.0 mmol/L 3.0 – 7.0Sodium 111 mmol/L 133 – 143Potassium 4.9 mmol/L 3.6 – 4.6

Bilirubin 166 µmol/L < 17Alk phos 175 U/L 21 - 92ALT 450 U/L 5 – 40Albumin 24 g/L 35 – 55Total protein 72 g/L 62 – 80Globulin 48 g/L 22 - 36