water distribution intracellular 28l (66%) extracellular 14l (33%) plasma 3.5 l (8%) interstitial...
TRANSCRIPT
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
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