1. Salt and Water
SpR training July 2012
Roderick Warren

2. Salt and water physiology
 Aldosterone
 Vasopressin
 Where they act
 What they do
 What happens with the crisps and beer

3. Collecting duct
principal cell –
aldosterone and
ADH receptors

4. ADH release:
• Osmolality (responds
to 1% change)
• Effective blood volume
(responds to 5-10%
change)

5. Aldosterone release:
• Potassium
• Effective blood volume
(detected at JGA)
ENaC – epithelial sodium channel
NCCT – sodium-chloride cotransporter
NKCC2 – sodium-chloride-potassium
cotransporter

6. Other natriuresis pathways
ANP
 Release: atrial distension (and other triggers)
 Effects: increases GFR (affects renal blood
flow); decreases Na resorption by NCCT
BNP
 Similar to ANP
Pressure natriuresis

7. In the pub
1. Eat crisps and nuts Salt intake
Increased osmolality
ADH release
5. Feel thirsty, drink beer Fluid intake
Increased volume
Aldosterone suppressed
9. Go to loo Excrete salt and water

8. Sodium balance
 Recommended intake <100 mmol per day
– 6g sodium chloride per day
– 2.4g sodium per day
 Average intake 150-200 mmol per day

9. Sodium balance
IN
OUT
2 litres water
Water 2 litres water
150 mmol
salt Salt 150 mmol
salt

10. Causes of hyponatraemia

11. Pseudohyponatraemia?
 Incorrect measurement due to presence of lots
of lipid or protein
 e.g. hypertriglyceridaemia
 Often wrongly used to mean hyponatraemia
due to another osmotic substance

12. Non-hypotonic hyponatraemia
 Glucose  All draw water into blood
 Urea  Reduce serum osmolality
 Mannitol
 Ethylene glycol  Detect by discrepancy
between calculated and
actual osmolality
(PS basically, serum osmo = plasma osmo)
Bunting et al, Crit Care Med 1986; 14: 650

13. Calculated versus actual osmolality
 Na 122  Measured osmo 320
 K 4.0
 Urea 3.4  Gap 370-240=60
 Gluc 4.5
 Osmo = (122+4) x 2  Ethylene glycol
+ 3.4 + 4.5 intoxication
= 260

14. When to measure osmolality
 Reasonable practice in all cases
 But remember what it’s for:
– to diagnose a non-measured solute
– ethanol
– methanol
– ethylene glycol

15. Hyperglycaemia
 Osmotic effect of high glucose draws water into blood,
and dilutes sodium (and everything else)
 Correction factor
– 1 mmol/L Na = 3.5 mmol/L glucose
 Possibly more pronounced at glucose > 25 mmol/L
– 1 mmol/L Na = 1.4 mmol/L glucose
Ref Hiller et al, Am J Med, 1999; 106: 399. Penne et al Diabetes Care 2010; 33: e91.

16. Hyperglycaemia
Admission – simple Admission – HONK
hyperglycaemia
Na 124 Na 146
Glucose 45 Glucose 45
Urea 8.2 Urea 28.2
After IV insulin After IV insulin
Na 139 Na 160

17. Hypotonic hyponatraemia: causes
Shout them out

18. SIADH
Diuretics Glucocorticoid Heart failure
Primary adrenal failure deficiency Cirrhosis
Primary renal disease Pregnancy Nephrotic
Pseudohypoaldosteronism Reset osmostat syndrome
Excess water intake
GI loss (vomiting, diarrhoea)
Skin loss (burns, sweating)
Third space (pancreatitis)
Dietary deficiency (anorexia)

19. Hypovolaemic Euvolaemic Hypervolaemic
SIADH
Diuretics Glucocorticoid
Heart failure
Renal deficiency
Primary adrenal failure Cirrhosis
sodium Pregnancy
loss Primary renal disease Nephrotic
Reset osmostat
Pseudohypoaldosteronism syndrome
Excess water
intake
GI (vomiting, diarrhoea)
Other Skin (burns, sweating)
sodium Third space (pancreatitis)
loss Dietary deficiency
(anorexia)

20. Assessing volume status
Either:
Actual
 obvious
Dry Normal
 or euvolaemic
Dry 7 22
Clinical
Think you can do better?
Normal 8 21
 Two expert nephrologists
carefully reviewed 58 patients For detecting volume depletion:
with hyponatraemia
• sensitivity 47%
 Clinical judgement compared
• specificity 49%
with response to IV saline
Chung et al Am J Med 1987; 83: 905

21. Hypovolaemic hyponatraemia
Cause Clue
Diuretic Obvious
Primary adrenal Symptoms, signs, cortisol
Primary renal Renal failure, urine dipstick
D&V Usually obvious from history
Anorexia Usually obvious
Skin loss Usually obvious from context
“Third space” Uncommon

22. If in doubt
Diuretics
Renal sodium Primary adrenal failure
Urine Na not low
loss Primary renal disease
Pseudohypoaldosteronism
GI (vomiting, diarrhoea)
Other sodium Skin (burns, sweating) Urine Na low
loss Third space (pancreatitis) (<20 mmol/L)
Dietary deficiency (anorexia)

23. Diuretic-induced hyponatraemia
Gitelman syndrome (like
thiazide treatment) –
hypokalaemia, alkalosis,
hypocalciuria,
hypomagnesaemia
Bartter syndrome (like
loop diuretic) – alkalosis,
hypokalaemia,
hypovolaemia,
hypercalciuria

24. Diuretic-induced hyponatraemia
 94% of reported cases are with thiazides
 Rapid onset (hours-days) – longer with loops
 Why? Possible causes:
– patients on thiazides are in water balance or slight
water excess (perhaps due to ADH release)
– short half-life of loop diuretics (brief electrolyte
excretion, then avid retention)

25. Adrenal failure
 Aldosterone deficiency
– normally protects sodium (at expense of
potassium)
 Cortisol deficiency
– tonic inhibition of ADH
– profound cortisol deficiency causes SIADH-like
picture

26. Hypervolaemic hyponatraemia
 Usually clinically obvious
 Said to be dilutional (though I think poorly
understood)
 ADH stimulated by reduced stretch receptor
stimulus due to...
– poor cardiac output
– reduced intravascular volume

27. Hypothyroidism is not a cause
Serum sodium distribution
in 1000 hypothyroid
patients and 5000 controls
95% ranges:
 132-144 (hypothyroid)
 134-144 (control)
Hypothyroidism lowers
serum Na by 0.48 mmol/L
Warner et al, Clin Endo 2006; 64: 596.

28. Syndrome of inappropriate
antiduretic hormone

29. Causes of SIADH
Drug causes Non-drug causes
Tricyclic antidepressants; Malignancy:
Selective serotonin reuptake  most, but especially lung.
inhibitors; Infections:
Opioids;  pulmonary (pneumonia,
Antipsychotics (e.g. haloperidol, TB, empyema);
chlorpromazine, flupentixol,  cerebral (e.g. meningitis,
trifluoperazine); abscesses).
Dopamine agonists; Nervous system disease:
Nicotine;  haemorrhage;
MDMA (Ecstasy).  infarction;
Anti-epileptics (carbamazepine,  demyelination (e.g. MS,
valproate); Guillain-Barré).

30. Normal ADH release

31. Patterns of SIADH
a – Random
b – Non-suppressible
basal ADH levels, but
normal response to raised
plasma osmolality
c – Reset osmostat. ADH
rises in response to
plasma osmolality, but is
always higher than it
should be.

32. What happens in SIADH?
Syndrome of inappropriate
antidiuretic hormone
Why doesn’t the patient swell
up?

33. What happens in SIADH?
Compensatory
Inappropriate
mechanisms –
ADH
aldosterone etc
Salt and
Water Water water
Water retention excretion Water
Salt Salt Salt
Normal state Hyponatraemia Hyponatraemia
Tendency to Euvolaemia
hypervolaemia

34. Experimental SIADH
Leaf et al 1953 J Clin Invest 1953; 32: 868

35. Experimental SIADH
Leaf et al 1953 J Clin Invest 1953; 32: 868

36. SIADH in theory
Onset Maintenance Recovery
Serum sodium
concentration
24-hour
urine
sodium
excretion

37. SIADH in theory
1. Fluid intake is required to become hyponatraemic
2. During onset, urine sodium excretion is high
3. SIADH = euvolaemia with total sodium deficit
4. In steady state, urine sodium = sodium intake
5. Sodium intake is required to correct hyponatraemia
6. In recovery, urine sodium is low
 (as for recovery from hyponatraemia of any cause)

38. Limitations: urinary sodium
 Range of sodium intake 60-250 mmol
 Range of water intake 1200-4000 mL
 Urinary sodium concentration
– from 15 mmol/L to 208 mmol/L

39. Limitations: urinary osmolality
 “Urine osmolality < serum osmolality excludes SIADH”
 Average protein intake 70g/d = 350 mmol urea
 Average sodium + chloride = 300 mmol
 Average potassium = 60 mmol
 Total about 700 mmol
 Average urine osmo = about 3-400 mOsm/kg
http://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/19710023044_1971023044.pdf

40. SIADH may be steady state
Onset Maintenance Recovery
Average urine
osmo about
Serum sodium
3-400
concentration
24-hour
urine
sodium
excretion

41. Limitations: urinary osmolality
 Average urine osmo = about 3-400 mOsm/kg
 Maybe 6-800 on waking
 Maybe 200 after drinking

42. So how can we diagnose SIADH?
By ruling out other diagnoses.
But you can exclude if:
 random urine osmolality <100 mOsm/kg
 random urine sodium <20 mmol/L
 except in the recovery phase

43. Low urine Na (and osmo) during
recovery phase
Onset Maintenance Recovery
Serum sodium
concentration
24-hour
urine
sodium
excretion

44. Example 1
76-year old admitted with chest infection.
Clinically euvolaemic.
Day 1 2 3 4 5 6 7
S Na 130 125 118 117 119
S Osmo 260 250
S Urea 5.6 4.3 4.0 4.8
S Creat 65 68 58 63
S Cort 680
U Na 76
U Osmo 420

45. Example 1
 Hyponatraemia
 Clinically euvolaemic
 No renal failure
 Normal cortisol
 Non-low urine sodium and osmolality
 Could well be SIADH

46. Example 2
45-year old admitted with D&V.
Looks dry.
Day 1 2 3 4 5 6 7
S Na 130 125 118 117 119
S Osmo 260 250
S Urea 5.6 6.3 8.0 9.8
S Creat 65 68 98 123
S Cort 680
U Na <20
U Osmo 180

47. Example 2
 Hyponatraemia
 Clinically hypovolaemic
 Degree of renal failure
 Normal cortisol
 Low urine sodium and osmolality
 History of GI loss

48. Example 3
76-year old admitted with chest infection.
Clinically euvolaemic.
Day 1 2 3 4 5 6 7
S Na 130 125 118 117 119 124 130
S Osmo 260 250
S Urea 5.6 4.3 4.0 5.8 6.9 5.8 5.7
S Creat 65 68 58 73 76 68 65
S Cort 680
U Na <20
U Osmo

49. Example 3
 Hyponatraemia
 Clinically euvolaemic
 No renal failure
 Normal cortisol
 Low urine sodium DURING RECOVERY
 Uninterpretable

50. Example 4
66-year old with heart failure.
Oedematous.
Day 1 2 3 4 5 6 7
S Na 126 127 125
S Osmo 260 260
S Urea 9.6 11.3 12.0
S Creat 124 136 140
S Cort 680
U Na 40
U Osmo

51. Example 4
 Clinical picture is heart failure
 So that’s the diagnosis
 Non-low urine sodium excludes GI loss
 In steady-state, urine sodium = sodium intake,
including if hypervolaemic
 Fluid restriction is appropriate even if SIADH
superimposed

52. Treatment of hyponatraemia

53. Treatment of hypotonic, hypovolaemic
hyponatraemia
Hypovolaemic
Diuretics Treatment:
Renal Primary adrenal failure
sodium • Salt and water
loss Primary renal disease
Pseudohypoaldosteronism • +/- Glucocorticoids
GI (vomiting, diarrhoea)
Other Skin (burns, sweating)
sodium Third space (pancreatitis)
loss Dietary deficiency
(anorexia)

54. Treatment of hypotonic,
hypervolaemic hyponatraemia
Hypervolaemic Treat underlying cause:
Heart failure
• e.g. rate control, digoxin
Renal • e.g. sepsis
Cirrhosis
sodium
loss Nephrotic Remove fluid:
syndrome
• paracentesis
• diuretics?
Other
sodium Fluid restrict
loss

55. Treatment of hypotonic, euvolaemic
hyponatraemia
Euvolaemic Treat cause of SIADH:
SIADH • e.g. stop drug
Glucocorticoid
Renal deficiency • e.g. antibiotics or
sodium chemotherapy
Pregnancy
loss
Reset osmostat Fluid restrict:
Excess water intake Give drugs:
Other • demeclocycline
sodium
loss • vaptan

56. When is acute treatment needed?
Sodium Effect
130-135 Usually asymptomatic
120-130 Non-specific malaise
<120 Confusion, ataxia, headache
Lower Depressed consciousness,
seizures, death

57. When is acute treatment needed?
Acute vs chronic (> or < 48 hr)
 Acute: increased risk of cerebral oedema
 Chronic: increased risk of CPM
Condition
 Confusion, seizures, other neurology
Sodium concentration
 120 mmol/L is a common threshold
Pragmatism
 Availability of HDU/ICU, and of hypertonic saline

58. What is acute treatment?
Boluses of hypertonic saline
 If neurologically obtunded
 100mL bolus of 3% saline, up to three times
 Will raise serum Na by 5-6 mmol/L
Infusion of hypertonic saline
 0.5 ml/kg/hr
 Will raise serum Na by 7-10 mmol/L/24 hr
Mohmand et al Clin J Am Soc Nephrol 2007; 2: 1110

59. What about normal saline?
 Exacerbates hyponatraemia…?
Infusion of 2 litres
normal saline
Mean pre-treatment
Na 126; n=17
Saline seems to help
if urine osmolality
<500
Musch et al Q J Med 1998; 91: 749

60. What do you do in a normal UK
hospital?
Serum sodium = 117 mmol/L
 If significant neurological symptoms,
definitely admit to ICU
 Otherwise:
– send serum osmo, cortisol, urine osmo early
– zero oral fluid
– give 1 litre 0.9% saline initially
– monitor Na frequently

61. Rate of correction
Urgent correction needed e.g. seizures
 5-8 mmol/L in the first hour
First day
 8-12 mmol/L
First 48 hours
 12-18 mmol/L

62. Fluid restriction
In milder cases, begin at one litre
 More liberal restriction may be OK if previous
fluid intake was high
Very tight restriction may be needed
 E.g. 500ml or zero

63. Fluid restriction
Needs to be strict and tight
 Must be thirsty, or ineffective
 Will cause rise in urea/creatinine

64. What happens in SIADH?
Compensatory
Inappropriate
mechanisms –
ADH
aldosterone etc
Salt and
Water Water water
Water retention excretion Water
Salt Salt Salt
Normal state Hyponatraemia Hyponatraemia
Tendency to Euvolaemia
hypervolaemia

65. What happens in fluid restriction?
Aldosterone ↑
Fluid restriction ANP, BNP ↓
Dehydration Salt and water
Water retention Water
Water
Salt Salt Salt
Hyponatraemia Hyponatraemia Normal state (but
Euvolaemia Hypovolaemia a bit dry)

66. Demeclocycline
 Dose 600-1200mg daily
 Induces nephrogenic DI in 70% of cases
 Usually 2-3 days to take effect
– but can be dramatic onset
Problems
 Avoid if eGFR<30
 Can cause irreversible nephrotoxicity
 Nausea
 Photosensitivity
 Hypersensitivity to tetracyclines (anaphylaxis, urticaria)

67. Vaptans
 V2-receptor antagonists
 Directly inhibit ADH

68. Vaptans

69. Tolvaptan
SALT-1 and SALT-2 trials
 448 patients with hyponatraemia
 Euvolaemic or hypervolaemic
 CCF, cirrhosis, SIADH
 Randomized to:
– placebo
– tolvaptan 15mg od, increased as needed
Schrier et al N Eng J Med 2006; 355: 2099.

70. Vaptans
Schrier et al N Eng J Med 2006; 355: 2099.

71. Vaptans
Problems
 Few side effects – thirst, dry mouth
 Cost:
– £75-£150 per day
– £27,000 to £54,000 per year
– to raise serum Na by about 5 mmol/L
 Restricted use
– recurrent profound hyponatraemia

72. Urea
Osmotic diuretic
 Rapid entry into cells – avoids sudden plasma
volume explansion
 Barely penetrates brain – avoids cerebral oedema
 0.5 – 1 g/kg/day
Unavailable in UK
 10 cans of baked beans
 1kg meat

73. Why treat chronic hyponatraemia?
No decent long-term therapy
 Why bother?
 Long-term adaptation to hyponatraemia?
But possibly:
 Gait disturbance
 Falls
 Osteoporosis

74. Gait and hyponatraemia
Centre of pressure path,
while walking right to left
•Before correction (Na
124)
•After correction (Na 135)
Renneboog et al Am J Med 2006 119
e1-8

75. Profound cortisol deficiency
Causes SIADH-like picture (or just SIADH?)
 Cortisol is tonic inhibitor of ADH secretion
Acute reversal with glucocorticoid
 Rapid excretion of free water
 Rapid rise in serum sodium
 Risk of myelinolysis

77. Profound hyponatraemia needs
intensive monitoring
 Frequent checks of serum sodium
 Meticulous fluid balance
 If rising too rapidly consider:
– stop saline
– give dextrose
– desmopressin

78. Cerebral salt wasting
Described in neurosurgical patients
 Thought to be mediated by BNP (SIBNP?)
 Hyponatraemia post SAH
 Cue scratching of heads
 Is it SIADH?
 Is it CSW?

79. SIADH CSW
1. ADH ↑ 1. BNP ↑
causing water retention causing salt and water loss
2. Renin, aldo ↓ 2a. ADH ↑
causing salt and water loss causing water retention
2b. Renin, aldo ↑
salt and water retention
What’s the difference?
Fluid replete Potentially fluid deplete
Urine sodium ↑ or normal Urine sodium ↑ or normal
Maybe renin, aldo ↓ Maybe renin, aldo ↓
Treatment: fluid restrict or Treatment: saline
saline

80. SIADH and lung cancer
Prevalence?
 3/23 in a study from Kuwait
CXR
 In all
Further investigation e.g. CT
 If persistent
 If other symptoms/signs

81. Serum osmolality Low (<270) High
-treat cause
-urea, glucose, toxins
Fluid volume status
Deplete Replete Overloaded
-history of D&V? - treat cause
-diuretics? - CCF, liver
-cortisol?
Check cortisol, urine osmo, urine Na
Low urine osmo Replete
Low urine Na Non-low urine osmo
Look for GI loss Non-low urine Na
Normal cortisol
Probable SIADH – fluid
restrict