Dr. Shiva Mongolu

Consultant Physician & Endocrinologist

Hull & East Yorkshire Hospitals NHS Trust

To fluid restrict or

not..that is the question! A practical approach to the management of

hyponatraemia

Aims

⦿ Understand the physiology of Na regulation

⦿ How to identify the cause

⦿ How to diagnose SIADH

⦿ Efficacy of treatment options ● Fluid restriction

● 1.8% Saline/3% Saline

● Demeclocycline

● Tolvaptan

Questions

• How is the patient?

• Is it acute or chronic ?

• Is it SIADH or volume depletion ?

• Do I need to intervene ?

More questions • Fluid restrict or Saline ?

• How much fluid to restrict ? Does it work ?

• Do slow sodium tablets work ?

• When should I use Demeclocycline ?

• What about the expensive drug Tolvaptan ?

• When should I use hypertonic saline ? Is it 1.8% or 3% ?

Background ⦿ Most common endocrine abnormality

⦿ Incidence 15-30% of hospitalised patients

(Na<135 mEq/L)

⦿ Associated with increased mortality (twice likely to

die during their hospital stay [RR 1.95])

⦿ Gait instability and falls

⦿ Overly rapid correction can cause severe

neurological deficits and death (osmotic

demyelination syndrome or central pontine

myelinolysis)

Physiology

Sodium is therefore regulated by 3 mechanisms: 1) RAAS

2) ADH release

3) Thirst mechanism

Osmoregulation Volume regulation

What is sensed ? Plasma osmolality Effective circulating volume

How clinically

assessed?

Plasma[Na⁺], P osm History, Physical exam, urine

[Na⁺]

Sensors Hypothalamic

osmoreceptors

Carotid sinus

Atria

Afferent arteriole (glomerulus)

Effectors ADH

Thirst mechanism

Sympathetic nervous system

Renin-angiotensin-aldo

system

Natriuretic peptides

ADH

What is effected ? Water excretion (ADH)

Water intake (thirst)

Sodium excretion

Acute vs. Chronic

● Hyponatraemia > 48hours duration is chronic

● Assume hyponatraemia chronic unless definite history (marathon

runners, psychotic patients, ecstasy users)

● Suggested rate of correction

● no more than 0.5-1mmol/hr

● Less than 8-10 mmol/L in 24 hours

● Less than 18 mmol/L in 48 hours

● Danger of rapid correction

● Central Pontine Myelinolysis (osmotic demyelination syndrome)

Asymptomatic patients with chronic hyponatraemia have a low risk of

serious neurologic sequelae but a well-described risk of osmotic

demyelination with rapid correction

Do I need to intervene ?

Do I need to intervene ?

Rx Rapid correction Risk of ODS

No Rx Risk of cerebral edema Seizures Death

ACUTE HYPONATRAEMIA

brain edema marked, minimal

brain volume regulation

CHRONIC ASYMPTOMATIC

HYPONATRAEMIA

complete brain volume

regulation

minimal brain edema

CHRONIC SYMPTOMATIC

HYPONATRAEMIA

some brain edema, partial

brain volume regulation

Endocrine Cases – Case 1

⦿ 62 yr old lady referred with acute confusion, unsteadiness, falls; preceeded by vomiting & diarrhoea a week before

⦿ On Bendrofluazide for HTN

⦿ Clinically euvolemic, GCS 14, AMT 8/10

⦿ Na 103 K 4.5 Cortisol 982 TFT normal

⦿ Serum Osm 230 Urine Osm 630 Urine Na 18

⦿ Diagnosis = Volume depletion+BFZ+ ?SIADH

Treatment

⦿ 0.9% Saline 8-12 hrly + Slow Sodium

tablets

⦿ Na improved to 109 in 24 hrs, 118 in 48

hrs

⦿ Saline and Slow Na stopped

⦿ Na continued to improve and was 126

on day3

⦿ Discharged with OP fu

Case 1 – follow-up

⦿ Represented 1 week later with agitation,

emotional lability, unable to care for

herself and her husband

⦿ Quite tearful, drooling of saliva, slow

speech and agitation

⦿ Na 135

⦿ MRI Brain

‘Increased signal in basal ganglia bilaterally, including head of caudate nuclei and the putamina as well as pons consistent with central pontine myelinolysis’

Risk factors for ODS

⦿ Serum Sodium at presentation

⦿ Duration of hyponatremia

⦿ Rate of correction

More common in :

○ Alcoholism

○ Malnutrition

○ Advanced liver disease

How quickly should I correct?

• Rule 1 : Correct hyponatraemia at the rate at which it occurred

• Rule 2 : If duration of hyponatraemia unclear, always safer to assume chronic onset

• Rule 3 : If hyponatraemia of chronic duration (onset over weeks rather than days) – : – Maximum Na rise of 8-10mmol/L over 24 hours (max 2 mmols/hr)

– Preferably much slower if not significantly symptomatic

– Be more cautious with severe hyponatraemia (Na < 110)

• Once Na at safe level (i.e. 115-120) aim for gradual correction

What is the cause ?

• Hypertonic – Significant hyperglycaemia

• High glucose concentration draws fluid from intracellular to extracellular space

• Normotonic

– Severe hyperlipidaemia • High lipid levels result in reduced plasma fraction, therefore falsely low sodium concentration

• Hypotonic

Correction for hyperglycaemia 1.6 mmol Na for every 5 mmol increase in glucose. E.g. Patient with Na of 127, Glucose of 30mmol/L. After correction –> Na = 135

Hypotonic hyponatraemia

⦿ Hypovolemic hypotonic hyponatraemia

● Solute loss

● Cerebral salt wasting

● Salt wasting nephropathy

● diuretics

⦿ Hypervolemic

● Liver cirrhosis, heart failure, nephrotic

syndrome

⦿ Euvolemic hyponatraemia (SIADH)

Is this SIADH ?

⦿ Exclude hypovolemia

⦿ Adrenal insufficiency and

hypothyroidism excluded

⦿ Drug related

⦿ Reset osmostat

Hypovolemic hyponatraemia vs SIADH

Hypovolemic

hyponatraemia

SIADH

Serum osmolality

Low Low

Urine Osmolality

High High

Urine Na Low High

In SIADH – urine Na is usually > 30 mEq/L (20-40) In Hypovolemia – urine Na < 25 mEq/L (15-20) * Assuming not on diuretics, normal dietary salt intake

Hypovolemic hyponatraemia vs SIADH ⦿ Urine osmolality > 100 indicates impaired ability to

dilute urine

⦿ Usually secondary to raised ADH level

⦿ Note – raised ADH can be both appropriate or inappropriate

⦿ If in doubt, treat with 0.9% Saline 1000 mls over 10 hours

⦿ If Na improves, it indicates hypovolemia. If doesn’t change/falls, it is SIADH

Case 2

● 76 yr old male

● 4 day history of confusion and falls

● Fit and well

● Started on Citalopram and Zopiclone 2 weeks ago due to low mood and memory problems

● Examination unremarkable

● Na 112 K 3.2 normal renal function

● Serum osmo 230 Urine osm 283 urine Na 31

● TSH 1.3 SST normal

● CT Head – no acute infarction/haemorrage

Diagnosis ?

⦿ ? Drug-induced SIADH ? Volume depletion ⦿ Citalopram and Zopiclone stopped ⦿ Given 0.9% Saline slowly ⦿ Repeat Na 109 ⦿ Diagnosis ? What next ? ⦿ No improvement with fluid restriction

800mls/24hr ⦿ Confusion worsening , GCS 14/15 ⦿ Treated with 1.8% Saline 500 mls 50ml/hr ⦿ Na gradually improved to 124 and 132 at

discharge

Treatment options - SIADH

⦿ Treat the cause

⦿ Fluid restriction ( 800 – 1000 mls/day )

⦿ Slow Sodium tablets

⦿ Hypertonic Saline ○ 1.8% Saline 500mls, 50mls/hr

○ 3% Saline – only in ITU setting

⦿ Demeclocycline (600 – 1200 mg daily )

⦿ Tolvaptan (15-30 mg daily )

Fluid restrict or saline?

● Volume status unclear from clinical assessment ● 1000mls of 0.9% saline over 10hrs, measure urine and serum

sodium pre / post

● Severe hyponatraemia with acute neurological compromise ● Consider hypertonic saline (usually Na < 110 mmol/L)

● Dual diagnosis ● i.e. SIADH + depleted intravascular volume, e.g. in septic shock,

high-volume diarrhoea

● Initial treatment with 0.9% saline, may require intermittent hypertonic saline (1.8%) if large volumes of IV fluids required

Will fluid restriction work? General guidelines

⦿ restrict all intake consumed by drinking,not just water

⦿ aim for fluid restriction that is 500ml/d below the 24-hr urine output

⦿ do not restrict sodium intake Predictors of failure of fluid restriction*

⦿ high urine osmolality (>500 mOsm/kg H2O) ⦿ urine Na+K greater than serum [Na] ⦿ 24 hr urine output < 1500 ml/day ⦿ Increase in serum[Na] < 2mmol/day

*The urine/plasma electrolyte ratio: a predictive guide to water restriction. Furst H et al; Am J Med Sci 2000

Do slow sodium tablets work? ● SIADH vs salt wasting?

● Oral sodium tablets favored in neurosurgical units ● Role in transient aldosterone resistance?

● Does it help in SIADH? ● Excess sodium excreted in urine together with water ● Effect can be estimated from urine osmolality ● May be effective in mild SIADH (Na > 125, urine

osmolality < 500) ● Is not practical in patients with moderate to severe

SIADH as amount of oral sodium required is excessive

Effect of Slow Na in SIADH

⦿ Eg : patient with a urine osmolality of 400, taking

2 tablets QDS

⦿ 1 tablet of slow Na contains = 10mmol Na +

10mmol Cl (20 mmol solute)

⦿ 8 tablets = 160 mmol

⦿ Urine volume = 𝑠𝑜𝑙𝑢𝑡𝑒 𝑙𝑜𝑎𝑑

𝑢𝑟𝑖𝑛𝑒 𝑜𝑠𝑚𝑜=

160

400 = 0.4L = 400ml

⦿ Excess water excretion = 400 mls (160 mmol of

solute diluted in 400 ml of water gives osmolality

of 400)

Effect of Saline in SIADH

When to use Demclocycline?

⦿ Induces reversible nephrogenic diabetes

insipidus

⦿ Doses used in studies 600-1200mg daily

⦿ Effect takes atleast 72 hrs

⦿ Significant rise in 5-7 days

⦿ Risk of hypernatraemia and renal

impairment

⦿ Can be used in chronic SIADH

What about Tolvaptan?

Can be considered in the following situations ●Confimed SIADH, alternative diagnosis excluded AND

●Symptomatic Hyponatremia with Na < 125 not responding to fluid restriction (1000mls/24h) OR ●Na <125 despite fluid restriction (1000mls/24h) and discharge would be expedited with correction of hyponatremia

OR ●Definite acute onset significant hyponatremia with acute symptoms ( may consider direct treatment with tolvaptan rather than fluid restriction in select cases ) with history and findings in keeping with SIADH

How does Tolvaptan work? ⦿ Competitive ADH receptor antagonist (V2

receptor)

⦿ Causes selective water diuresis

⦿ Licensed for use in SIADH

⦿ Dose 15-30mg

⦿ Concern about possibility of too rapid correction

⦿ 1.8% of patients in SALT trials had Na rise >12 mmol in first 24 hrs

⦿ No report of CPM with Tolvaptan

* For inpatient use only after review by Endocrine Consultant

Tolvaptan

Tolvaptan not to be used in the following

circumstances: 1.Serum Na < 110 mmol/L*

2.GCS < 14 ( unless chronically low GCS )*

3.Concurrent septic shock or hypovolemic shock in addition to

pre-existing SIADH

4.Patient unable to take oral or NG fluids ( on parenteral

nutrition/IV fluids only )

* 3% Hypertonic Saline should be used cautiously in ITU in

these patients

Hypertonic saline

⦿ Indicated in patients where there is :-

● EITHER urgent need to correct symptomatic

hyponatraemia

● OR other measures unavailable/have failed

● OR dual diagnosis (hypovolaemia + SIADH) requiring

high volume / continuous IV fluid replacement therapy

⦿ Will correct hyponatraemia regardless of

underlying aetiology (however if SIADH, Na will

drop back down on stopping hypertonic saline if no

other intervention)

Hypertonic saline

Option of 1.8% saline and 3% saline 1.8% saline (308mmol of Na/L) ⦿ 500ml bags readily available (ITU/NeuroITU/pharmacy if not kept on ward)

⦿ Can be safely given via peripheral cannula on ward (only via slow infusion through a pump)

⦿ For treatment on ward - 500mls at 50mls/hr with repeat measurement of Na at the end of infusion to assess response in serum Na.

⦿ E.g. to get Na from 120 to 128, may require 1000mls of 1.8% saline/24hrs for total of 48hrs

Summary ⦿ Two main causes of hypotonic hyponatraemia in

inpatients are : hypovolemia and SIADH

⦿ Assume hyponatraemia chronic unless there is clear evidence

⦿ When treating hyponatraemia, consider the risks of cerebral edema vs risks of rapid Rx

⦿ If severe hyponatraemia (Na<110mmol/L) or neurological compromise, urgent correction with 3% Saline (irrespective of the cause) in ITU setting

⦿ Contact Endocrine team for advice

Thank you Questions ?