RDE SSU Lecture 3 Focus on Sodium

1. RDEH Journal Club 5th
May 2006
Disorders of Sodium Balance
Clinical Review BMJ Vol 332
25th
March 2006
Rebecca Reynolds
(+) A case of ? Salt Poisoning
Presented by John O’Connor

2. Sources of Information
• Consensus from systematic reviews
(medline search)
• Less than a dozen RCT’s on treatment of
Sodium disorders
• Despite frequency, no review in the
Cochrane Library

3. Control of Sodium Balance
• Maintained in tight limits 135 – 145
mmol/L
• Na +HCO3+Cl accounts for 80% ECF
Osmolality
• [2*Na] + Glucose + Urea
• Main determinant [Na] = plasma water
content

4. Daily Water Balance
Under Normal Conditions

5. Pathways Through Which Dehydration
Stimulates Hypothalamic Thirst Centers

6. Relationship Between Sodium Intake,
Water Balance and Hormones

7. Series of Events in Water Intoxication

8. Role of ADH in Water Balance

9. Summary of Hormones Involved
in Water Balance

11. Biochemical Homeostasis

13. Etiologies of Hyponatremia
Poor Intake of Sodium
Increased Urinary Loss of Sodium
Diuretics
Proximal RTA
Aldosterone deficiency/resistance
Increased GI Loss of Sodium (Fluid loss
must be followed by repletion with free water).
Vomitting
Diarrhoea
Increased Transcutaneous Loss of
Sodium (Fluid loss must be followed by
repletion with free water).
Excessive Intake of Water (1° polydipsia)
Psychosis
Decreased Urinary Excretion of Water
Decreased GFR
Increased ADH
Decreased effective circulating volume
True volume depletion (any cause)
Apparent volume depletion
Heart failure
Cirrhosis
SIADH
Reset osmostat
Transmembrane Shift of Water
Hyperglycemia
Primary Sodium Loss Primary Water Excess

16. Symptoms
• Relate to severity and rapidity of fall
• Creates an osmotic gradient between the ECF and ICF in
brain cells
• Water moves into brain cells, oedema raising intracranial
pressure
• Nausea and malaise 125 –130 mmol/L
• Headaches, lethergy disorientation 115-120
• If fall is rapid: seizures, coma permenent brain damage,
brain stem herniation
• If gradual, brain regulates itself, Transporters initiate
movement of NaCl KCl, Glutamate, Taurine, myo-inositol
to ECF, moving water with them

17. History, Examination
Investigation
• Spot Urine Na
• > 30 mmol/L = hypovolaemic
hyponatraemia
• < 30 mmo/L = extrarenal loss
• In Hypervolaemic hyponatraemia Ur Na >
30

18. • Box 2: Examination and investigations in patient with hyponatraemia
Evaluationof volume status
• Skin turgor
Pulse rate
Postural blood pressure
Jugularvenous pressure
Consider central venous pressure monitoring
Examinationof fluid balance charts
General examination for underlyingillness
• Congestive cardiac failure
Cirrhosis
Nephrotic syndrome
Addison'sdisease
Hypopituitarism
Hypothyroidism
Porphyria
• Investigations
• Urinarysodium
Plasma glucose and lipids*
Renal function
Thyroidfunction
Peak cortisol during short synacthen test
Plasmaand urine osmolality
If indicated: chest x ray, and computedtomography and magnetic resonance
imaging of head and thorax

19. Management
• Try to avoid gining the patient central
pontine myelinolytis
• Do not alter S Na > 12 mmol/L 24 hrs
• Little evidence that using hypertonic saline
3% NaCL, in asymptomatic patients is wise
• Even more heroic is to use the above with a
loop diuretic like furosemide (increases free
water clearance)

20. Management
• Fluid restriction (< 1 L day) initial approach
• No trials have ever been done
• Demeclocycline (inhibits ADH working on
kidney) drug of choice especially inn
SIADH
• New drugs aquaretics (tolvaptan) are ADH
antagonists at clearing free water. Good in
SIADH, Cirrhosis, CHF

21. Etiologies of Hypernatremia
Primary Sodium Excess
Excess Intake of Sodium
Decreased Urinary Excretion of
Sodium
Hyperaldosteronism
Primary Water Loss
Poor Intake of Water
Impaired access to water (i.e. infants, elderly
patients with dementia or whom are bedbound)
Impaired thirst sensation
Hypothalamic lesions
Increased Urinary Loss of Water
ADH deficiency (Central DI)
ADH resistance (Nephrogenic DI)
Increased GI Loss of Water
Increased Transcutaneous Loss of Water
Transmembrane Shift of Water (most often due to
rapid production of intracellular lactate)

23. Hypernatraemia
• Not common
• Usually reflects net water loss
• Severe symptoms Na > 158 mmol/L
• Sensation of intense thirst (protective)
• Anorexia, muscle weakness, nausea early
• Later stupor, coma, brain shrinkage and rupture
• SAH

24. Box 3: Classification of hypernatraemia
Hypovolaemia
•Dermal losses—for example, burns, sweating
Gastrointestinal losses—for example, vomiting, diarrhoea, fistulas
Diuretics
Postobstruction
Acute and chronic renal disease
Hyperosmolar non-ketotic coma*
Hypervolaemia
•Iatrogenic (hypertonic saline, tube feedings, antibiotics containing
sodium, or hypertonic dialysis)
Hyperaldosteronism
Euvolaemia
•Diabetes insipidus (central, nephrogenic, or gestational)
Hypodipsia
Fever
Hyperventilation
Mechanical ventilation

25. Management
• If hypernatraemia has developed over a
short period (hours), rapid correction (1
mmol/Hr) improves prognosis
• If longstanding slow correction is
recommended
• Central Diabetes Insipidus treat with
desmopressin

26. Summary of Hormones Involved
in Sodium Balance

27. Guilty or Not Guilty
LORD JUSTICE RICHARDS
MR JUSTICE PENRY-DAVEY
and
HER HONOUR JUDGE GODDARD QC
(sitting as a Judge of the Court of Appeal
Criminal Division
Between:
Regina
Respondent
- v -
Angela Alison Gay
Ian Anthony Gay
Appellants

28. • On his admission to hospital on 8 December 2002, Christian
age 3 was suffering from hypernatraemia, an abnormally high
concentration of sodium in his blood. His blood (or plasma)
sodium on admission to the Russells Hall Hospital was at the
dangerously high level of 184 millimoles per litre ("mmol/l"). A
normal level is in the region of 140 mmol/l. He was given an
intravenous saline solution (which, on the face of it, may seem
odd, but is explained by the need to bring down the level of
sodium gradually in order to reduce the risk of damage to the
cells). By the time of his transfer to the Birmingham Children's
Hospital in the evening of 8 December the level was down to
173 mmol/l. Although the regime adopted at that hospital was
expected to continue to bring the level down, it remained at or
above 170 mmol/l for the next 24 hours, i.e. throughout 9
December. This was the "plateauing effect" to which reference
is made in the expert evidence considered below. On 10-11
December the level did fall further but did not get below 157
mmol/l, still much higher than normal.

29. PM Report
• There was evidence of trauma to Christian's head.
The post mortem revealed 11 sub-scalp bruises
which appeared to be recent. There were areas of
subdural haemorrhaging and bruising, and the brain
was grossly swollen. There were also retinal
haemorrhages.
• There was an area of infarction (in effect, death of the
muscle) in the left ventricle of the heart, which had
probably occurred while Christian was in hospital. It
was the kind of injury that might be caused by a heart
attack in an adult, but was most unusual in a young
child. There was also some older infarction of a
capillary muscle elsewhere in the heart.

30. Sodium Balance: Intake & Excretion
Figure 20-11: Homeostatic responses to eating salt

31. Prof Haycock (Prosecution)
• Two of the possible causes of such a high level of sodium have
been ruled out:
• (1) severe dehydration, PH suggested expansion in the
extracellular (low for blood urea and creatinine, haemoglobin
and plasma albumin.)
• (2) known pre-existing metabolic disorders or other diseases.
• Very sophisticated testing was done … to rule out all known
existing disorders which might have caused that high level of
salt.
• Evidence drinking lots just before admission
• Usually has to be persuaded to drink
• PH opinion: Hypernatraemia was due to ingestion of salt (30-
40g)
• Every reason to suppose that the kidneys were normal.

32. • He should have excreted the excess sodium
back to normal. Yet the sodium readings
showed that the level did not fall as expected
(in particular, there occurred the plateauing
effect mentioned above), and a further set of
readings for the "fractional excretion of
sodium" showed likewise that the excess
sodium was not being excreted.
•
• PH thought that the most likely explanation
for this was severe cardiac dysfunction. The
premise being that cardiac dysfunction would
increase Aldosterone secretion and sodium
resorbtion

33. Congestive Heart Failure (CHF) and the effective circulating volume.
In CHF there can be chronic ↑ ECF volume (oedema) as an
adaptation to decreased cardiac output because the effective
circulating volume is low.
Cardiac Output and renal perfusion pressure are low
⇓
↑ renin, AII, aldo, ↑ sympathetic output
⇓
more Na+
retention and more oedema
⇓
atrial stretch → restore cardiac output and perfusion of
vital organs at the expense of expanded ECF volume
This new steady state depends on the persistent error signal of ↑ECF.
ANP doesn’t correct this because the anti-natriuretic hormones
increase Na+
reabsorption proximal to the inner medullary collecting
duct where ANP works. That is, not enough gets to the IMCD to
have an impact.

34. Defence Dr Walters retired CP (Bristol)
• Rejects the view that the hypernatraemia was caused by
ingestion of salt.
• First, there was the failure to excrete the load of salt allegedly
taken.
• Aldosterone Normal and heart showed some ventricular
damage not enough to cause increase in Aldosterone (but post
mortem sample)
• Walters pointed out trials of salt ingestion leading to a low
aldosterone
• Provided the regulatory systems are working normally, the body
rejects excess sodium. Christian would have had to ingest an
enormous amount of salt for his plasma sodium concentration to
be so high. That should have led to a high rate of excretion of
sodium. There was a high rate initially, but it tailed off and was
back at a more normal rate after about 12 hours. It should have
continued at the higher rate for at least 48 hours after
admission.

35. • Normally administering water will lower sodium
• First, the excretion of sodium in the urine is
enhanced: (dependent on the amount of urine
formed)
• Secondly, water is also retained through the action
ADH: the effect is to dilute the concentration of
sodium in the ECF.
• The fluid balance charts show that towards the end
Christian was being given only very dilute solutions of
salt, and he passed large volumes of urine, but
without a correspondingly high concentration of
sodium.
• At some stage during his admission he retained a lot
of water, with some sodium, but still the sodium
concentration did not fall below about 160 mmol/l.

36. • Sodium concentration is regulated by the
hypothalamus by osmoreceptors, known collectively
as the osmostat, which trigger the release of ADH,
and water retention
• Thus, if the plasma sodium concentration rises, ADH
is released so that a small volume of concentrated
urine is formed, the amount of water retained in the
body is increased and the sodium concentration is
thereby brought down.
• If the sodium concentration falls, the release of ADH
is inhibited so that a large volume of dilute urine is
passed, the amount of water retained in the body is
reduced and the sodium concentration is thereby
brought up.
• A high sodium concentration results in the sensation
of thirst,(Osmostat) which leads to drinking. In
concert with the increased action of ADH on the
kidney tubules, this enables lost water to be replaced.
• The normal osmostat setting is 140 mmol/L

37. Case reports suggest the osmostat setting can be disturbed.
Most of the reported cases involve physical damage to the
hypothalamus, e.g. as a result of surgery.
There are other, less common, cases in which no identifiable cause
has been found: the description "idiopathic" is given to such
cases.
Most of those other cases involve the downward resetting of the
osmostat, so that the patient has a persistently low sodium
concentration.
The upward resetting of the osmostat, resulting in a high sodium
concentration, is much rarer.
There are, however, two documented cases of it: a 1985 paper by
Gill, Baylis and Burn, A case of 'essential' hypernatraemia
due to resetting of the osmostat, and a 1987 paper by
Thompson, Freeman, Record and Baylis, Hypernatraemia
due to a reset omsostat for vasopressin release and thirst,
complicated by nephrogenic diabetes insipidus.
• W's opinion: there is no reason in principle why the same
event could not happen in a child,

38. • Second possibility: Reduced sensitivity of the
osmostat, such that the release of ADH or
increase in thirst occurs much more slowly
than with a normal osmostat.
• Combined with an abnormality in his thirst
mechanism.
• It may be that Christian did not know what
thirst was until the late stages when his
plasma sodium concentration went
abnormally high and he displayed frantic thirst
on the morning he died

39. • Routine tests in 1999 and 2000 (1 yr) showed normal
sodium levels (135 to 140 mmol/l).
• W’s hypothesis therefore required something to have
happened thereafter to the hypothalamus to cause
the osmostat to reset to a higher level
• W considered that a reset could occur at any time
(the trigger being unknown)
• Change of this kind would not have affected
Christian's ability to live a normal life.
• Still difficult, however, to explain the sudden onset of
acute illness, with the sodium level of 184 mmol/l on
admission to hospital.
• W considered that this was possible if Christian had
been running with a plasma sodium level of, say, 160
or 165 mmol/l and then for some reason had become
water depleted. If that happened there would be a
surge in the plasma sodium and it could reach 184
mmol/l without clinical signs of dehydration.

40. • Professor Haycock response
• He could not see an event or illness in Christian's
history that might have led to a change in the
osmostat setting.
• In all the cases of osmoreceptor dysfunction that he
had seen himself or had studied in the literature, the
patients had shown little or no thirst; and in none had
there been anything like the frantic thirst displayed by
Christian on 8 December
• Nor did any of them involve the kind of catastrophic
collapse seen in this case.
• Christian's thirst on 8 December suggested a rapid
rise in sodium concentration over a very short space
of time. Ingestion of salt would do it. So would lack of
access to water, but it would take a few hours at least
to get to the point of severe thirst.

41. There then occurred the following important exchange:
• "Q. … Now just as you at trial … postulated heart
failure as an explanation, do you agree that what Dr
Walters has done is a quite legitimate exercise in
postulating an alternative hypothesis; is that right?
• A. Yes.
• Q. And you are not in a position, are you, to say
that he is wrong?
• A. No, I am not."
Professor Haycock was asked a number of questions about
why he had not mentioned the other possible cause of
hypernatraemia,
A number of other matters were canvassed with Professor
Haycock in cross-examination, including criticisms of
certain of his analyses and calculations

42. Summing UP
• Mr Mansfield (Defence). Not only was there a
remarkable combination of features, including
trauma to the head and hypernatraemia,
• The damage to the heart was in itself a highly
unusual feature in a child of this age.
• The prosecution case on the cause of the
hypernatraemia relied not simply on the existence of
that damage to the heart, but on the hypothesis that
there was heart failure sufficient to (increase
Aldosterone )override the body's normal mechanisms
for the excretion of excess sodium. (to explain the
plateau)

43. The verdict
For the reasons we have
given, the appeals are
allowed on the ground
relating to fresh evidence
and the appellants'
convictions of
manslaughter on count 2
are quashed. We will
hear submissions from
counsel on whether a
retrial should be ordered.

44. Guilty v Not Guilty
• Why no Ur Osmolality or Ur Sodium
measurements
• If W is right and his normal running Na 165
mmol/L, trying to force it lower with infusions
would precipitate CPM??
• Injuries to head, could he have had Central DI
??
• What if he had become so hypovolaemic that the
low BP stimulated increase in Aldosterone. Only a
small amount of salt ingestion could have pushed
the sodium which would happen very quickly