Hyponatraemia on ICU

• Sodium should be around 134 - 146 mmol/litre
• Usually you have around 58 mmol in your body per kilo of body weight
• Daily requirement is 2 mmol per kilo
• Serum osmolality 280–295 mOsm kg⁻¹
• 99% of sodium is reabsorbed in the proximal tubule and loop of Henle
• Most of the fine tuning happens in the distal tubule and collecting ducts

• Any change in sodium or water level will produce a slight alteration in extracellular fluid osmolality
• You only need an increase of around one or two percent to stimulate the posterior pituitary to start producing antidiuretic hormone (a.k.a. vasopressin)
• This triggers V2 receptors in the distal convoluted tubule and collecting duct, shoving aquaporin-2 channels into the tubular membrane and increasing water reabsorption
• The patient also feels rather thirsty
• This leads to increased water retention and intake, and brings the sodium concentration back down
• If on the other hand the osmolality drops, then ADH secretion is reduced and fluid is excreted, and the sodium concentration increases

Voila, sodium levels are nicely controlled.

• Hypovolaemia means less sodium passes through the distal convoluted tubule
• This induces renin secretion from the juxtaglomerular apparatus
• Renin then converts angiotensinogen into angiotensin 1
• ACE in the lungs then converts 1 to 2
• Angiotensin 2 tells the adrenal cortex to release aldosterone
• This tells the collecting ducts to increase sodium retention
• This drags water along for the ride
• Baroreceptors also sense reduced vascular volume and trigger ADH release
• More water is retained as described above

It's quite an effective mechanism too, demonstrated by the huge range of possible urine osmolalities, from around 50 to 1300 mOsm per kg.

This one is a normal response of the body's fluid retention mechanism.

• You're injured with massive haemorrhage, or disastrously dehydrated
• Your body desperately tries to retain fluid
• To do this the renin-angiotensin-aldosterone system is running overtime and ADH has shoved as many aquaporins into the collecting duct as possible
• This is all entirely appropriate as a survival mechanism
• You're retaining as much salt as possible in order to retain fluid
• You're also now incredibly thirsty, and probably drink a whole load of hypotonic water, rather than isotonic fluid
• With this and the ADH working full tilt, you manage to retain a little more water than sodium, and so you become hyponatraemic
• But you're still dehydrated, so you're hypovolaemic
• And you've still lost salt in the original bleed/diarrhoea, so you're hypotonic

Hence we call this hypotonic, hypovolaemic hyponatraemia.

This process, and this hypovolaemic, hypotonic hyponatraemia, happens in anyone with major loss of extracellular fluid.

• Diarrhoea
• Burns
• Haemorrhage
• Third spacing

The patient's urinary sodium will be low in non-renal losses, because the kidneys are working and are appropriately retaining salt.

The patient needs salt and water replacement, along with treatment of the underlying cause.

This one is not a normal physiological response - it's inappropriate fluid retention.

• Something has activated inapproprate RAAS and ADH activity (such as heart failure or cirrhosis making the kidneys think there isn't enough blood volume)
• The body inappropriately retains salt and water (giving small volumes of concentrated urine with a low sodium)
• You become hypotonic and hyponatraemic, but you're fluid overloaded

The patient needs loop diuretics and/or ACE inhibitors

Causes:

• Heart failure
• Cirrhosis*
• Nephrotic syndrome (low protein = third spacing = intravascular depletion = RAAS and ADH activation)

*This is a double whammy, because not only does the liver disease cause low blood pressure and hypoperfusion of the kidneys, it also means the ADH that is inappropriately released then doesn't get broken down either.

This is a normal response to a pathalogical state of fluid excess.

Dilute urine means a urine osmolality of less than 100

• The sodium level in the body may be normal, but is diluted by the extra water
• The body is sensibly trying to get rid of all the excess fluid, while retaining the salt as much as possible
• The urine is less than 100 mOsm/litre and is 'maximally dilute', and has low sodium as this is all being sensibly retained

Causes:

• Beer potomania*
• Water intoxication

*Beer is lots of water and a bit of carbohydrate, with not much sodium, so when you drink lots of it, you metabolise the carbohydrate and suppress any protein break down, reducing the urea production.

This means you don't have much in the way of solute to put into the urine, and therefore struggle to produce enough urine, as it is already maximally diluted.

This leads to fluid retention and hyponatraemia.

It's actually really hard to overwhelm a healthy kidney's ability to excrete water, so usually hyponatraemia due to excessive water intake is usually in the context of existing renal problems.

For example psychogenic polydipsia usually occurs in patients with another cause for iatrogenic SIADH such as SSRIs.

This is still hypotonic hypovolaemic hyponatraemia but for a different reason.

• Something is making the kidneys malfunction
• They're losing salt and water into the urine
• The urinary sodium is therefore high (>20mmol/litre)

Causes

• Diuretics
• Renal failure
• Chronic pyelonephritis
• Saltwasting nephropathy
• Aldosterone deficiency
• Nephrocalcinosis
• Proximal renal tubular acidosis
• Ketonuria
• Cerebral salt wasting syndrome*

The diuretic causes sodium and water loss, triggers ADH release and therefore a bit of fluid retention, but no sodium retention.

The reason thiazides are particularly bad is because they don't mess up the osmotic gradient in the medulla (which furosemide does mess up).

As a result with thiazides you can still reabsorb water fairly well, but not sodium, and so you get high urinary sodium and hyponatraemia.

The patient still needs salt and water replacement, and treatment of the underlying condition or removal of the offending medication.

*Exam answer - Cerebral salt wasting syndrome gives you a dehydrated, inappropriately polyuric patient while SIADH gives you a fluid replete or overloaded and inappropriately oliguric patient.

This is a patient with far too much water on board who is still retaining fluid, but unlike the CCF/Liver patients we've discussed above, their kidneys aren't churning out renin to retain salt and water, they're actively trying to lose salt and water, but something endocrine is stopping them from getting rid of enough water.

They have a high urinary osmolality of greater than 100.

• SIADH
• Glucocorticoid deficiency
• Hypothyroidism

• If you have Addisons then you lose your aldosterone production
• This means there's no stimulation of the ENaC channel in the collecting duct
• Therefore you can't reabsorb as much sodium (and excrete potassium)
• Then add in the fact that cortisol is also an ADH inhibitor, so if you're not producing enough cortisol you've got more active ADH floating around
• This leads to water retention and high urinary sodium

This can either be a primary adrenal problem or as a result of stopping steroid therapy too quickly, or by giving too much spironolactone.

The treatment is steroids.

• Unclear exactly how this works
• It's probably a bit like heart failure, where decreased cardiac output means less kidney perfusion
• The kidneys and baroreceptos get upset and more ADH is produced, causing fluid retention

The main thing is to test hyponatraemic patients' thyroid function, and give thyroxine if needed.

• There is pathological production of antidiuretic hormone, for whatever reason (trauma/surgery/infection etc)
• Their ion excretion mechanisms still work, so they're able to produce urine with a high urinary sodium
• But as you give them more and more fluid they simply retain the water and excrete the salt

Neuro

• Trauma
• SAH
• Surgery
• Stroke
• Epilepsy
• Meningitis
• Cancer

Respiratory

• Sarcoidosis
• Abscess
• TB
• Pneumonia

Neoplastic

• Small cell lung cancer
• GI cancer
• GU cancer
• Lymphoma
• Mesothelioma

Drugs

• Proton pump inhibitors
• SSRI
• TCA
• Valproate
• Keppra (levetiracetam)
• Oxytocin (very chemically similar to ADH)
• Ecstasy

Other

• Acute intermittent porphyria
• Guillain-Barré syndrome
• HIV
• VR2 gene gain-of-function mutation (nephrogenic SIADH)

• Hyponatraemia with low serum osmolality
• Urine osmolality higher than serum osmolality
• Urine sodium greater than 20 mmol/L
• Normal hepatic, cardiac and endocrine function
• No other causes
• No hypovolaemia
• Gets better with water restriction

• ANP and BNP are released by damaged brain (and heart) tissue
• This produces a natriuresis and profound dehydration with salty urine
• The distinguishing point is the patient is inappropriately dehydrated with high urine output.

SIADH, on the other hand, causes water retention and low urine output.

ADH is high in both CSW and SIADH, but in CSW it's in response to the dehydration, and therefore appropriate.

This terrifying and irreversible condition manifests after 48 hours to a week, with symptoms including confusion, dysphagia, dysarthria, paralysis and seizures.

• It's not really called 'pontine' any more, because it can happen anywhere that myelin is present
• It can also be triggered by other osmotically active molecules like glucose or urea
• It can happen even without giving hypertonic saline, if the patient happens to auto-correct too quickly
• Generally only happens below a sodium of 120

Patients at risk:

• Severe malnutrition
• Alcoholism
• Diuretic use
• Liver transplant patients (enormous risk factor)

The cause is an excessively rapid rise in extracellular fluid osmolality.

Rate of correction:

• Your brain is far better at adapting to hypotonic extracellular fluid than it is to hypertonic fluid
• Hence you can use this to your advantage with hypertonic saline in raised ICP
• The most important number is less than 6mmol per 24 hours

Yes good - you do need to alter the sodium concentration rapidly, but by much less than you think.

They're seizing because they've got cerebral oedema and raised ICP, thanks to our closed-box skull and the good old Monroe-Kellie doctrine.

So you only need to bring the intracranial fluid volume down by a tiny percentage to reduce the pressure by a lot.

This means you can give some hypertonic saline initially just to drag some volume out of the brain and get symptom control, (aim to increase sodium by a max of 2-4% over 30 minutes) and then you can slowly bring that level up to something a little more normal over the next few days.

That's where we get the 150 ml of 3% saline over 20 minutes that we keep batting on about.

• 58 year old woman collapses at home and is shown to have extradural and subarachnoid haemorrhage on CT
• Transferred to neurosurgical centre for decompression
• Day six post operative bloods show a sodium of 119 and patient is profoundly oliguric
• Euvolaemic on examination
• Serum osmolality 274
• Urine osmolality 190
• Urinary sodium 38 mmol/litre

This is SIADH, classically kicking in 5 - 7 days after neurosurgery, subarachnoid haemorrhage or head trauma.

Treatment:

• Fluid restrict to less than one litre per day
• Demeclocycline if needed, to induce a spot of nephrogenic diabetes insipidus
• Tolvaptan (V2 receptor antagonist) should only be considered by senior endocrinologist if all else fails

• 22 year old male with vomiting and diarrhoea
• Tachycardic and hypotensive
• Sodium 128, potassium 3.4, urea 12 and creatinine 163
• Serum osmolality 275
• Urine osmolality 344
• Low urinary sodium

This is a dehydrated patient with high urine osmolality and high urinary sodium.

This is a completely normal response to profound dehydration. He has lost water and salt, but proportionately more salt as the kidneys desperately tried to retain water.

You still need to test TSH to rule out hypothyroidism.

Treatment

• IV fluids (don't forget potassium)
• Stop any meds that might be making things worse (diuretics)

THIS IS THE ONE THAT GETS EXAMINED A LOT

• 68 year old man has just had a TURP
• He's become confused and short of breath in recovery
• You do a blood gas
• Na 121, K 3.2, slight metabolic acidosis with respiratory compensation
• Serum osmolality low
• Bibasal crackles

This is TURP syndrome

• 1.5% glycine was classically used for irrigation
• It gets absorbed into the blood, and drags the osmolality of the serum down (1.5% glycine is hypotonic at around 200 mOsm/kg)
• This causes an initial hypervolaemic hypotonic hyponatraemia
• Then the glycine causes an osmotic diuresis
• This leads to a later hypovolaemic hypertonic hyponatraemia

Treatment:

• Usually self limiting
• Furosemide can help
• Sodium replacement might be required

• 72 year old woman with heart failure and alcohol excess presents with shortness of breath and abdominal distension
• Sodium 109
• Potassium 5.3
• Creatinine 144
• Serum osmolality 246
• Urine osmolality 300
• Urinary sodium 20

This is fluid overload, or hypervolaemic hypotonic hyponatraemia

The heart failure causes bad perfusion, which makes the adrenals and kidneys think the body is dehydrated, which causes secondary hyperaldosteronism, and inappropriate fluid retention.

Treatment:

• Loop diuretics (furosemide infusion can be titrated to an acceptable rate of sodium increase)

• Demyelinolysis
• Hypernatraemia and hyperosmolality
• Fluid overload and heart failure
• Hypokalaemia and metabolic acidosis
• Dilutional coagulopathy
• Phlebitis
• Renal failure
• Rebound intracranial hypertension
• Seizures
• Intracranial haemorrhage

• Dialysis can be risky in hyponatraemia, as the dialysate has around 145 mmol/L of sodium, which will gleefully and enthusiastically equilibrate with the blood, causing an intolerably rapid correction of the sodium level, and a shredded pons
• It is possible to make up a hypotonic dialysate and use dialysis to correct hyponatraemia safely, but please don't bring this up in your exam - you'll regret it

• Hyperlipidaemia
• Hyperproteinaemia

This is simple maths-fudging.

Salt can't dissolve in fat or protein, so if there's loads of either of these two in the blood, they'll artificially inflate the apparent volume of blood, and cause the concentration of sodium to seem low.

This is referred to as isotonic pseudohyponatraemia

• Sodium is measured in an ABG machine using indirect ion selective electrode (ISE) sampling which is affected by this problem
• Lab readings can often use a direct ion-sensitive electrode which isn't fooled by the fat or protein

Something even more tonic than sodium has entered the chat.

• Glucose - drags fluid into vascular compartment and dilutes sodium down
• Mannitol (initially, but then becomes hypernatraemia after all the water gets diuresed out)
• Alcohol intoxication (technically, but usually an alcoholic is hyponatraemic because of the fluid overload and high triglycerides)
• Glycine