Download Water Balance and Hyponatraemia

Clinical Science (1979) 56,5 17-522
EDITORIAL REVIEW
Water balance and hyponatraemia
D. B. M O R G A N A N D T. H. T H O M A S
Department of Chemical Pathology, University of Leeds, The General Infirmary, Leeds, U.K.
Water balance and its control in man in health and
disease has been the subject of many studies and
reviews (Berl, Anderson, McDonald & Schrier,
1976; Robertson, 1977). However, disorders of
water balance, in particular hyponatraemia, continue to cause difficulty in clinical practice.
Our aim is to consider the physiological purpose
of water balance, and what makes the patient ill
when water balance is abnormal, and on that basis
to attempt to define the relationship between hyponatraemia and the clinical effects of water overload.
Water depletion and thirst are not discussed here.
Physiological background
Verney (1948) showed that hyperosmolar solutions of sodium chloride and other substances
injected into the carotid artery caused a decrease in
urine flow and indirect evidence suggested this was
due to an increased secretion of antidiuretic
hormone from the pituitary gland. He suggested
that there were specialized cells (osmoreceptors)
within the distribution zone of the internal carotid
artery, which responded to a change in the
osmolality of the extracellular fluid and caused a
change in the secretion of antidiuretic hormone.
Robertson, Klein, Roth & Gordon (1970)
developed an assay which allowed them to examine
the effect of hyperosmolar solutions on the plasma
concentration of the human antidiuretic hormone,
arginine vasopressin (AVP). These studies taken
together demonstrate that when the plasma
osmolality is increased with saline, sucrose or
Abbreviation: AVP, arginine vasopressin.
Correspondence: Dr D. B. Morgan, Department of
Chemical Pathology, University of Leeds, The Martin
Wing, The General Infirmary, Leeds.
36
mannitol, there is an increase in plasma AVP.
However, when the plasma osmolality is increased
with urea or glucose, which can enter cells, there is
no increase in plasma AVP. These findings demonstrate that it is not an increased plasma osmolality
which stimulates AVP secretion, but that a gradient
of osmolality between cells and extracellular fluid is
probably at least a step in the stimulus to changing
AVP secretion. In these acute experiments this
gradient of osmolality will be temporary as water
will move rapidly from the cells to re-establish
equilibrium. It is therefore likely that it is the
resulting reduction in cell volume, which, in some
unknown way, leads to the increased secretion of
AVP (Verney, 1948; Leaf, 1962). We have put cell
volume as the controlled variable at the centre of a
feedback system, which is therefore not osmoregulatory although it will respond to an acute change
in the osmolality of the extracellular fluid.
The relations between these changes in plasma
osmolality and urine water flow are determined by
the components of the system, that is the relation
between plasma osmolality and AVP secretion (the
osmoreceptor response) and the relation between
AVP and urine osmolality (the renal response).
The osmoreceptor response can be defined in terms
of the plasma osmolality at which plasma AVP increased (‘threshold’ or setting) and the subsequent
change in plasma AVP for a given change in
plasma
osmolality
(‘the
responsiveness’)
(Robertson, Mahr, Athar & Sinha, 1973; but see
Moses, 1978). These responses are such that the
urine flow can be halved or doubled if the plasma
osmolality is changed by only 1% (2 mosmol/kg),
which is a change in plasma sodium of only 1
mmol/l (Verney, 1948; Robertson, Shelton &
Athar, 1976). The fall in plasma sodium which
causes symptoms (10-15 mmol/l) is almost always
5 17
518
D. B. Morgan and T. H . Thomas
due to a defect within the system, as a very large
intake of water (20 litredday) would be required to
produce it if the system was normal. When
symptoms do occur they are neurological and are
probably due to water-loading of cells, particularly
the brain (Arieff, Llach & Massry, 1976). The
renal system is inadequate to deal with water depletion because of the inevitable loss of water through
the skin and lungs and it is for this reason that
increased water intake through thirst is an essential
response to increased osmolality of the body fluids.
The experiments of Verney and Robertson and
his colleagues were acute ones concerned with
transient uncompensated responses of the system,
whereas many clinical problems are chronic states
due to long-standing defects in the system. In
health the osmolality of body fluids and the cell
volume are kept almost constant at some chosen
value (steady state), which requires that water
excretion equals water intake. This is achieved by
setting the urine osmolality to what is required for
balance. Patients with a chronic hyponatraemia
may contain relatively too much water, but the
situation is not deteriorating otherwise the patient
would not have survived. The patients are therefore in a steady or near-steady state, albeit an
abnormal one (Levinsky, Davidson & Berliner,
1958; Leaf, 1962; Flear, 1970). In addition they
may have few or no symptoms in spite of chronic
hyponatraemia and hypo-osmolality (Wynn &
Rob, 1954; Arieff et al., 1976).
A comparison of chronic hyponatraemia with
acute hyponatraemia therefore suggests that two
changes have taken place. If the initial water
retention and hyponatraemia was due to an
excessive AVP secretion and increased urine osmolality, then if the AVP secretion continued, a steady
state could only be achieved if the excretion of
water increased. Theoretically this could be
achieved by an increase in the intake and excretion
of osmotically active molecules, or by a fall in the
renal responsiveness to AVP so that the urine
osmolality falls to what is required for balance. A
reduced renal responsiveness to AVP is common
among patients with gross hyponatraemia (Leaf,
1962; Thomas, Morgan, Swaminathan, Ball & Lee,
1978).
The other change in chronic hyponatraemia is
indicated by the absence or diminished severity of
symptoms (Wynn & Rob, 1954; Arieff et al.,
1976). This suggests that either the brain cells have
adapted in some way to the increase in cell volume
or that some mechanism has allowed the cell
volume to return to normal. Arieff et al. (1976)
have reviewed the evidence that in chronic water
overload the osmolar and water content of the
brain cells gradually fall. If this happened, then
even if the plasma and cell osmolality remained low
the brain cell volume (and plasma AVP) would
return towards normal and symptoms might
become less severe or even disappear.
The changes within the system which can cause
severe acute or chronic hyponatraemia include
changes in the osmoreceptor responsiveness to
plasma osmolality and the presence of non-osmolar
stimuli to AVP secretion (Leaf, 1962). On the other
hand, changes in the biological half-life of AVP or
in the renal responsiveness to AVP do not cause
severe hyponatraemia because they can be compensated for by a change of AVP secretion (or
thirst), which requires only a small change in
plasma osmolality.
Acute clinical problems
Acute water overload with acute hyponatraemia
only happens when a defect in the system reduces
the patient’s ability to excrete water. When a
healthy person is given large volumes of water and
injected with antidiuretic hormone (Stormont &
Waterhouse, 1961) water is retained, the plasma
osmolality and plasma sodium concentration fall,
and the person develops headache and fatigue progressing to cramps, nausea, vomiting, diarrhoea
and delirium. Acute water overload has also been
produced in some women given large doses of
Syntocinon intravenously in glucose solution
(Morgan, Kirwan, Hancock, Robinson, Howe &
Ahmad, 1977), and in these patients, as in others
with acute water overload, the symptoms can
progress to convulsions, unconsciousness and even
death. There is some relationship between the
amount of water retained, the magnitude of the fall
in plasma sodium concentration and the presence
and severity of symptoms (Swales, 1975; Arieff et
al., 1976; Morgan et al., 1977). Acute severe hyponatraemia (less than 120 mmol/l, which is an
average fall of 20 mmol/l) is probably always
associated with symptoms (Arieff et al., 1976; De
Troyer & Demanet, 1976).
There are many acute clinical situations where
AVP secretion is sustained, in spite of a progressive
fall of plasma osmolality, so that there must be a
non-osmotic stimulus to AVP secretion. This
happens after surgery, and when these patients are
given solutions with a high water to sodium ratio
the urine osmolality is too high for water balance
(Thomas & Morgan, 1979), water is retained and
Water balance and hyponatraemia
plasma osmolality and sodium concentration fall.
Other non-osmotic stimuli to AVP secretion
include ‘volume depletion’, low blood pressure
(Robertson er al., 1976) and fainting (Davies,
Slater, Forsling & Payne, 1976). Acute excessive
AVP secretion is also present in patients with
hyponatraemia and chest infection (Thomas et al.,
1978) and may account for the hyponatraemia of
glucocorticoid deficiency (Boykin, De Torrente,
Erickson, Robertson & Schrier, 1978).
Where there is a non-osmotic stimulus to AVP
and also in patients given Syntocinon, the presence
and magnitude of the water retention (and thus of
hyponatraemia) will of course depend on the water
intake (or composition of intravenous fluids) as
well as on the magnitude of the defect in the
system, and the excess of AVP.
The excessive AVP secretion produced by a
progressive fall in extracellular fluid volume has
been discussed in terms of the priorities of
maintaining osmolality and extracellular fluid
volume. Osmolality is said to have the top priority
at first during progressive volume depletion, and is
then sacrificed as water is retained through an
increased secretion of AVP, which minimizes the
further fall in extracellular fluid volume. There is
some doubt about the first part of this response
(Brennan & Malvin, 1977; Weitzmann,
Farnsworth, MacPhee, Che Ching Wong & Bennet, 1978), but volume deficits of more than 1015% are, on average, associated with increased
plasma AVP (Roberston et al., 1976). The response may vary greatly between persons so that
some allow osmolality to fall from the beginning of
volume depletion, and others maintain it until
volume depletion is extreme (Morgan, Ball,
Thomas & Lee, 1978). The stimulus to AVP secretion in volume depletion may be stimulation of
volume receptors in the left atrium and the same
mechanism might explain the sustained AVP
secretion in patients with chest infections. A
minority of patients taking diuretics develop hyponatraemia (Fichman, Vorherr, Kleeman & Telfer,
1971; Ghose, 1975; Kennedy, Mitchel & Hofforand, 1978). The hyponatraemia is unlikely to be
due to a movement of sodium into the cells (Alam,
Wheeler, Wilkinson, Poston, Golindano & Williams, 1978) and it may be that it happens in those
persons who retain water even when the volume
(saline) depletion is small. Acute hyponatraemia
may also arise because of a limit to urine flow, due
to acute or chronic renal failure or an increased
reabsorption of sodium in the proximal tubules, due
to, for example, saline depletion. The acute hypo-
5 19
natraemia of beer drinkers is probably due to a
combination of a large water intake and a limit to
urine flow due to saline depletion (Demanet,
Bonnyns, Bleiberg & Stevens-Rochmans, 1971).
The clinical effects of acute gross water overload, as in the case of Syntocinon treatment, are
dramatic and easily detected. The symptoms are
easily missed in other situations where the
symptoms are less dramatic, vague and nonspecific, and can be attributed to the patient’s
illness (Wynn & Rob, 1954). When symptoms
have been sought in patients with hyponatraemia
they have frequently been present, although nonspecific (Arieff et al., 1976: Kennedy et al., 1978).
Chronic clinical problems
Chronic hyponatraemia has many causes and is
common (Flear & Singh, 1973), but its physiological basis, clinical effects and significance for
clinical management are less well defined than for
acute water overload and hyponatraemia. As we
have emphasized, the patients must be in a steady
state, and are often free of symptoms.
There are several possible primary changes
within the system which can lead to chronic
hyponatraemia. One type of change is an ectopic
production of AVP (as from a carcinoma of the
lung). Such production should be uncontrolled
(but, see Padfield, Morton, Brown, Lever,
Robertson, Wood & Fox, 1976). There may be few
chronic symptoms, but the patient may present
with acute confusion, convulsions and coma, perhaps due to a sudden change in water intake,
plasma osmolality and brain cell volume. However,
chronic hyponatraemia with lowered plasma osmolality is much more commonly associated with a
variety of conditions such as heart failure, various
neurological disorders, hypothyroidism and drugs,
particularly chlorpropamide and carbemazapine
(Moses & Miller, 1974). In these conditions, AVP
secretion continues in response to a non-osmolar
drive such as volume depletion (when the plasma
AVP may be normal or raised) or a lower setting or
threshold of the osmoreceptor (when the plasma
AVP would be normal). When there is a nonosmolar drive to AVP secretion the normal
feedback system should be switched off,and there
should be an excessive reduction in the plasma
osmolality after a water load. In the case of
resetting, the patient’s response to a water load
should be normal, and this has been demonstrated
in a few patients (DeFronzo, Goldberg & Zalman,
1976).
520
D. B. Morgan and T. H. Thomas
Robertson et al. (1976) have attempted to
identify and distinguish some of these mechanisms
of chronic hyponatraemia on the basis of the
relationship between plasma AVP and plasm
sodium, before and during an infusion of hyperosmolar saline.
The chronic hyponatraemia of heart failure is
usually attributed to excess AVP due to volume
depletion (Leaf, 1974; Swales, 1975), but it
probably has several mechanisms (Takasu, Lasker
& Shalhoub, 196 1). In hypothyroidism the plasma
AVP is greatly increased, even if there is little fall in
the plasma sodium (Skowsky & Kikuchi, 1978).
This raised plasma AVP may be due to an
increased half-life of AVP, but the presence of a
normal plasma sodium in some patients indicates a
change in osmoreceptor setting and the presence of
a steady state indicates a diminished renal responsiveness to AVP. Reduced renal responsiveness is
observed in patients with other causes of hyponatraemia, and is therefore probably a secondary
phenomenon (Leaf, 1962).
A change in renal function leading to an absolute
limit in water excretion cannot be the cause of
chronic hyponatraemia as a steady state cannot be
achieved.
There is a view that in some patients the chronic
hyponatraemia is due to ‘sick cells’. This is a
controversial subject and the writings on it are
made difficult by a lack of clear definitions. The
general concept is that changes in cell function can
cause the cells to gain sodium and lose potassium
and lead to hyponatraemia. Three separate cell
events may be involved: an increase in membrane
permeability, a decreased activity of the sodium
pump and a decrease of cell molecules. Flear
& Singh (1973) suggested that an acute increase
in cell permeability allows certain molecules to
leave the cells and accumulate in the extracellular
fluid. Retention of water will lead to a normal plasma
osmolality and acute hyponatraemia. This combination is observed in some very ill patients after
surgery or burns (Flear & Singh, 1973; Tindall &
Clark, 1976) but has not been detected in patients
with chronic hyponatraemia and heart failure
(Leaf, 1974). Diminished activity of the sodium
pump will cause the cells to gain sodium and lose
potassium, but will not necessarily cause hyponatraemia (Flear & Singh, 1973; Swales, 1975).
The type of ‘sick cells’ which might be relevant
to chronic hyponatraemia would be produced by a
reduction in cell molecules, due to increased loss of
diminished production (Flear & Singh, 1973). In
the new steady state, there would be a normal
cell volume but a low cell and plasma osmolality.
The plasma AVP would be the same as in
healthy people and would be what was expected
for the cell volume, although it would appear excessive when related to the plasma sodium and plasma
osmolality. There would be a normal response to
variation in water intake. This form of ‘sick cells’
would therefore cause ‘resetting’ of the system,
which was the functional change detected by
Robertson et al. (1976) in a third of their patients
with chronic hyponatraemia. In clinical practice it
is difficult to distinguish between a primary
reduction in cell molecules (‘sick cells’), an
excessive secretion of AVP (from volume
depletion) and an intrinsic failure of urinary dilution as the cause of the chronic hyponatraemia in
conditions such as heart failure. The major
theoretical difference is in the response of the
system to a change in plasma osmolality, which
should be normal if the cause is ‘sick cells’. Leaf
(1962, 1974) excludes ‘sick cells’ and resetting as
the cause of the chronic hyponatraemia of heart
failure, because his patients were unable to excrete
a water load normally. However, even when the
primary event is an excess of antidiuretic hormone, the fall in plasma sodium is sometimes more
than expected from the water retention alone
(Morgan et al., 1977), so that water-loaded cells
may become ‘sick cells’. There may therefore be
more than one cause of hyponatraemia in the individual, and at least in heart failure the dominating
cause may be different in different patients.
For these and other reasons, it has been
suggested that the term inappropriate secretion of
ADH should be abandoned (Swales, 1975;
Thomas et al., 1978), and a simpler descriptive
terminology, such as hyponatraemia of heart
failure, should be used until the pathophysiology of
the condition in general and in the individual has
been clearly defined.
An alternative view of the system
We suggest that the physiological and clinical
observations indicate that the system which is
usually described as a sytem for water balance or
osmolality control can more correctly and usefully
be regarded as a system to control cell volume, particularly the volume of brain cells (Flear & Singh,
1973; Leaf, 1974).
An overall view of ‘fluid and electrolyte balance’
is that there are systems which separately set and
regulate extracellular fluid volume and intracellular volume. The extracellular fluid volume is
Water balance and hyponatraemia
set and regulated through the mechanisms which
regulate total body sodium, which remains extracellular and at a particular osmolality determines
extracellular fluid volume. The intracellular volume
is set by pumping sodium out of cells to counter the
volume-expanding effects of the cell molecules
(MacKnight & Leaf, 1977), but is regulated
acutely through changes in total body water and in
chronic disease at least in part through changes in
the cell molecules.
Pathophysiology of the system
The major clinical effects of a relative water overload and depletion are probably due to changes in
brain cell volume. Unfortunately, the clinical effects
such as headache, confusion and irritability are illdefined, non-specific, difficult to quantify, even
crudely, and are often ignored in ill patients. What
is required is some measure or index of cell volume.
Changes in cell volume will be associated with
changes in plasma osmolality and sodium.
However, a fall in plasma sodium concentration
can happen without a fall in plasma osmolality
when there is an accumulation of lipids or proteins
or an accumulation of molecules other than
sodium, such as glucose or urea, or intracellular
molecules which have leaked into the extracellular
fluid (Flear & Singh, 1973).
Chronic hyponatraemia without symptoms
could be due to a primary increase in AVP secretion with a secondary reduction in cell molecules
and a normal cell volume, or to a primary reduction in cell molecules with a normal cell volume
(‘sick cells’). In both cases the cell volume is
normal and treatment designed to remove water
from the cell (which is, of course, the correct treatment in acute water overload with symptoms)
would reduce the cell volume below normal and the
patients would become ill (Thomas et al., 1978).
The difference between these two causes of chronic
hyponatraemia is that the patient with a primary
increase in AVP secretion is unable to respond to
an increase in water intake, and is liable to acute
water overload with symptomatic acute or chronic
hyponatraemia with symptoms, The symptoms
would presumably disappear when the plasma
sodium increased to its previous low value and to
raise it to a normal concentration would be to make
the patient ill.
References
ALAM, A.N., WHEELER,P., WILKINSON,S.P., POSTON,L.,
GOLINDANO,C. & WILLIAMS,R. (1978) Changes in the
electrolyte content of leucocytes at different clinical stages of
cirrhosis. Gut, 19,650-654.
521
ARIEFF, A.I., LLACH,F. & MASSRY,S.G. (1976) Neurological
manifestations and morbidity of hyponatraemia: correlation
with brain water and electrolytes. Medicine, 55,121-129.
BERL, T., ANDERSON,
T.J., MCDONALD,K.M. & SCHRIER,
R.W. (1976) Clinical disorders of water metabolism. Kidney
International, 10,117-132.
BOYKIN,
J., DE TORRENTE,A., ERICKSON,
A., ROBERTSON,
G.
& SCHRIER,R.W. (1978) Role of plasma vasopressin in impaired water excretion of glucocorticoid deficiency. Journal
of Clinical Investigation, 62,738-744.
BRENNAN,
L.A. & MALVIN,
R.L. (1977) Concentrations of antidiuretic hormone in plasma during human sodium restriction. Nephron, 19,284-287.
DAVIES,R., SLATER,J.D.H., FORSLING,M.L. & PAYNE,N.
(1976) The response of arginine vasopressin and plasma renin
to postural change in normal man, with observations on syncope. Clinical Science and Molecular Medicine, 51, 267274.
DEFRONZO,R.A., GOLDBERG,M. & ZALMAN,S. A. (1976)
Normal diluting capacity of hyponatraemia patients: reset
osmostat of a variant of the syndrome of inappropriate antidiuretic hormone secretion. Annals of Znternal Medicine, 84,
538-542.
DEMANET,J.C., BONNYNS,M., BLEIBERG,H. & STEVENSROCHMANS,
C. (1971) Coma due to water intoxication in
beer drinkers. Lancet, ii, 1115-1 117.
DE TROYER,A. & DEMANET,J.C. (1976) Clinical, biological
and pathogenic features of the syndrome of inappropriate
secretion of antidiuretic hormone: a review of 26 cases with
marked hyponatraemia. Quarterly Journal of Medicine, 45,
521-531.
FICHMAN,
MP., VORHERR,H., KLEEMAN,C.R. & TELFER,N.
(197 1) Diuretic induced hyponatraemia. Annals of Znternal
Medicine, 15,853-863.
FLEA&C.T.G. (1970) Electrolyte and body water changes after
trauma. Journal of ClinicalPathology, 23 (Suppl. 4), 16-31.
FLEAR,C.T.G. & SINGH,C.M. (1973) Hyponatraemia and sick
cells. British Journal of Anaesthesia, 45,976-994.
GHOSE, R.R. (1975) Hyponatraemia and diuretics (Letter).
Lancet, i,578-579.
KENNEDY,
P.G.E., MITCHELL,D.M.& HOFFBRAND,
B.I. (1978)
Severe hyponatraemia in hospital in-patients. British Medical
Journal, ii, 1251-1253.
LEAF, A. (1962) The clinical and physiologic significance of the
serum sodium concentration. New England Journal of Medicine, 261,2630.
LEAF,A. (1974) Hyponatraemia (Letter). Lancet, i, 1119-1 120.
LEVINSKY,
N.G., DAVIDSON,D.G. & BERLINER,R.W. (1958)
Changes in urine concentration during prolonged administration of vasopressin and water. American Journal of
Physiology, 196,45 1-456.
MACKNIGHT,A.D.C. & LEAF,A. (1977) Regulation of cellular
volume. Physiological Reviews, 51, 5 10-573.
MORGAN,D.B., KIRWAN,N.A., HANCOCK,K.W., ROBINSON,
D., HOWE,J.G. & AHMAD,S. (1977) Water intoxication and
oxytocin infusion. British Journal of Obstetrics and
Gynaecology, 84,6- 12.
MORGAN,D.B., BALL,S.R., THOMAS,T.H. &LEE,M.R. (1978)
Sodium losing renal disease: two cases and a review of the
literature. QuarterIy Journal of Medicine, 47.2 1-34.
MOSES,A.M. (1978) Is there an osmotic threshold for vasopressin release? (Letter). American Journal of Physiology,
234, ~ 3 3 9 - ~ 3 4 1 .
MOSES,A.M. & MILLER,M. (1974) Drug induced dilutional
hyponatrzemia. New England Journal of Medicine, 291,
1234-1239.
PADFIELD,P.L., MORTON,J.J., BROWN, J., LEVER,A.F.,
ROBERTSON,
I.S., WOOD,M. & Fox, R. (1976) Plasma arginine vasopressin in the syndrome of antidiuretic hormone
excess associated with bronchogenic carcinoma. American
Journal ofMedicine, 61,825-831.
ROBERTSON,
G.L. (1977) The regulation of vasopressin function in health and disease. Recent Progress in Hormone
Research, 33,333-385.
522
D. B. Morgan and T. H . Thomas
ROBERTSON,
G.L., KLEIN,L.A., ROTH,J. & GORDEN,P. (1970)
Immunoassay of plasma vasopressin in man. Proceedings of
the National Academy of Sciences USA., 66, 12981305.
KOBBRTSON,
G.L., MAHR,E.A., ATHAR,S. & SINHA,T. (1973)
Development and clinical application of a new method for the
radioimmunoassay of arginine vasopressin in human plasma.
Journal of Clinical Invesfigafion,52,2340-2352.
ROBERSTON,
G.L., SHELTON,R.L. & ATHAR,S. (1976) The
osmoregulation of vasopressin. Kidney Infernational, 142537.
SKOWSKY,
W.R. & KIKUCHI,T.A. (1978) The role of vasopressin in the impaired water excretion of myxedema.
American Journal of Medicine, 64,613-621.
STORMONT,J.M. & WATERHOUSE,
C. (1961) The genesis of
hyponatraemia associated with marked overhydration and
water intoxication. Circulation, 24, 19 1-203.
SWALES,J.D. (1975)Sodium Metabolism In Disease, chapter 5.
Lloyd-Luke, London.
TAKASU,T., LASKER,N. & SHALHOUB,
R.J. (1961) Mechanisms of hyponatraemia in chronic congestive heart failure,
Annals of Infernal Medicine, 55,368-383.
THOMAS,T.H. & MORGAN,D.B. (1979) Post-surgical hyponatraemia. BrifishJournal of Surgery (In press).
THOMAS,T.H., MORGAN,D.B., SWAMINATHAN,
R., BALL,S.B.
& LEE, M.R. (1978) Severe hyponatraemia: a study of 17
patients. Lancef,i, 621-624.
TINDALL,S.F. & CLARK, R.G. (1976) Hyponatraemia in
surgical practice. BrifishJournal of Surgery, 63,150.
VERNEY,E.B. (1948)The antidiuretic hormone and the factors
which determine its release. Proceedings of fhe Royal Sociefy
of London, Series B, 135.25-106.
WEITZMAN,
R.E., FARNSWORTH,
L., MACPHEE,R., CHECHING
WONG& BENNET,C.M. (1978) Effect of opposing osmolar
and volume factors on plasma arginine vasopressin in man.
Mineral ElecfrolyteMetabolism, 1.43-47.
WY”, V. & ROB,C.G. (1954)Water intoxication: differential
diagnosis of the hypotonic syndromes. Lancef, i, 587-594.